Medicaments for the treatment or prevention of fibrotic deiseases

ABSTRACT

The present invention relates to the use of indolinones of general formula 
     
       
         
         
             
             
         
       
     
     substituted in the 6 position, wherein
 
R 1  to R 5  and X are defined as in claim  1 , the isomers and the salts thereof, particularly the physiologically acceptable salts thereof, as a medicament for the prevention or treatment of specific fibrotic diseases.

The present invention relates to a new use of indolinones of generalformula

substituted in the 6 position, the tautomers, the diastereomers, theenantiomers, the mixtures thereof and the salts thereof, particularlythe physiologically acceptable salts thereof.

BACKGROUND

Compounds of the above general formula I, the tautomers, thediastereomers, the enantiomers, the mixtures thereof and the saltsthereof, particularly the physiologically acceptable salts thereof, havebeen described in WO 01/27081 and WO 04/13099 as having valuablepharmacological properties, in particular an inhibiting effect onvarious kinases, especially receptor tyrosine kinases such as VEGFR2,PDGFRα, PDGFRβ, FGFR1, FGFR3, EGFR, HER2, IGF1R and HGFR, as well ascomplexes of CDK's (Cyclin Dependent Kinases) such as CDK1, CDK2, CDK3,CDK4, CDK5, CDK6, CDK7, CDK8 and CDK9 with their specific cyclins (A,B1, B2, C, D1, D2, D3, E, F, G1, G2, H, I and K) and to viral cyclin(cf. L. Mengtao in J. Virology 71(3), 1984-1991 (1997)), and on theproliferation of cultivated human cells, in particular endothelialcells, e.g. in angiogenesis, but also on the proliferation of othercells, in particular tumour cells.

However, none of these compounds have been described for their use inthe treatment or prevention of the fibrotic diseases referred to in thepresent invention.

Remodeling is a normal response to tissue injury and inflammation thatis observed in many tissues throughout the body. After resolution of theinflammation and repair of tissue damage, the tissue is generallyreturned to its original condition. Excessive uncontrolled tissue repairor the failure to stop remodeling when it is no longer required leads tocondition known as fibrosis. Fibrosis is characterized by excessivedeposition of extracellular matrix components and overgrowth offibroblasts. Fibrosis can occur in all tissues but is especiallyprevalent in organs with frequent exposure to chemical and biologicalinsults including the lung, skin, digestive tract, kidney, and liver(Eddy, 1996, J Am Soc Nephrol, 7(12):2495-503; Dacic et al., 2003, Am JRespir Cell Mol Biol, 29S: S5-9; Wynn, 2004, Nat Rev Immunol,4(8):583-94). Fibrosis often severely compromises the normal function(s)of the organ and many fibrotic diseases are, in fact, life-threateningor severely disfiguring, such as idiopathic pulmonary fibrosis (IPF),liver cirrhosis, scleroderma, or renal fibrosis. Treatment options forthese diseases are often limited to organ transplantation, a risky andexpensive procedure.

A large body of literature implicates the platelet-derived growth factor(PDGF), fibroblast growth factor (FGF), vascular endothelial growthfactor (VEGF), epidermal growth factor (EGF), and transforming growthfactor beta (TGFb) growth factor families in the induction orpersistence of fibrosis (Levitzki, Cytokine Growth Factor Rev, 2004,15(4):229-35; Strutz et al., Kidney Intl, 2000, 57:1521-38; Strutz etal., 2003, Springer Semin Immunopathol, 24:459-76; Rice et al., 1999,Amer J Pathol, 155(1):213-221; Broekelmann et al., 1991, Proc Nat AcadSci, 88:6642-6; Wynn, 2004, Nat Rev Immunol, 4(8):583-94).

PDGF, EGF and FGF family members are potent mitogens for mesenchymalcells such as smooth muscle cells, myofibroblasts and fibroblasts(Benito et al., 1993, Growth Regul 3(3):172-9; Simm et al, 1998, BasicRes Cardiol, 93(S3):40-3; Klagsburn, Prog Growth Factor Res, 1989,1(4):207-35; Kirkland et al., 1998, J Am Soc Nephrol, 9(8):1464-73), thevery cells which supplant normal tissue in fibrosis and are believed toplay a role in tissue remodeling (Abboud, 1995, Annu Rev Physiol.,57:297-309; Jinnin et al., 2004, J Cell Physiol, online; Martinet etal., 1996, Arch Toxicol 18:127-39; Desmouliere, Cell BiologyInternational, 1995, 19:471-6; Jelaska et al., Springer SeminImmunopathol, 2000, 21:385-95).

Inhibition of PDGF attenuates both liver fibrosis and lung fibrosis inexperimental models, suggesting fibrosis in different organs may have acommon origin (Borkham-Kamphorst et al., 2004, Biochem Biophys ResCommun; Rice et al., 1999, Amer J Pathol, 155(1):213-221). An EGFreceptor kinase inhibitor was also active in this lung fibrosis model.Three-fold overexpression of an EGF family member, HB-EGF, in mousepancreas islets was sufficient to cause development of fibrosis in boththe exocrine and endocrine compartments (Means et al., 2003,Gastroenterology, 124(4):1020-36).

Similarly, FGF1/FGF2-deficient mice show dramatically decreased liverfibrosis after chronic carbon tetrachloride (CCl4) exposure (Yu et al.,2003, Am J Pathol, 163(4):1653-62). FGF expression is increased in humanrenal interstitial fibrosis where it strongly correlates withinterstitial scarring (Strutz et al., 2000, Kidney Intl, 57:1521-38) aswell as in a model of experimental lung fibrosis (Barrios et al., 1997,Am J Physiol, 273 (2 Pt 1):L451-8), again lending credence to the ideathat fibrosis in various tissues has a common basis.

In addition, elevated levels of VEGF have been observed in severalstudies in persons with asthma (Hoshino et al., 2001, J Allergy ClinImmunol 107:1034-39; Hoshino et al. 2001, J Allergy Clin Immunol107:295-301; Kanazawa et al. 2002, Thorax 57:885-8; Asai et al., JAllergy Clin Immunol 110:571-5, 2002; Kanazawa et al., 2004, Am J RespirCrit Care Med, 169:1125-30). Inducible expression of VEGF in atransgenic mouse model induces an asthma-like phenotype, edema,angiogenesis and smooth muscle hyperplasia (Lee et al., 2004, Nature Med10:1095-1103).

Finally, TGFb stimulates production of extracellular matrix proteinsincluding fibronectin and collagens and is believed to play an importantrole in fibrosis in many tissues (Leask et al., 2004, FASEB J18(7):816-27; Bartram et al., 2004, Chest 125(2):754-65; Strutz et al.,2003, Springer Semin Immunopathol, 24:459-76; Wynn, 2004, Nat RevImmunol, 4(8):583-94). Inhibitors of TGFb production and signalingpathways are active in a number of fibrosis animal models (Wang et al.,2002, Exp Lung Res, 28:405-17; Laping, 2003, Curr Opin Pharmacol,3(2):204-8).

As summarized above, several growth factors are upregulated in fibrosisand the inhibition of a single factor seems to reduce the severity offibrosis in the fibrosis models.

SUMMARY OF THE INVENTION

Surprisingly, we found that the compounds of above general formula I areeffective in the treatment or prevention of specific fibrotic diseases.

The present invention thus relates to the use of the compounds of abovegeneral formula I for the preparation of a medicament for the treatmentor prevention of specific fibrotic diseases.

The present invention also relates to a method for the treatment orprevention of specific fibrotic diseases, by administration to a patientin need thereof of a pharmaceutical composition comprising a compound ofabove general formula I, together with a pharmaceutically suitablecarrier. The expression “patient” is meant to comprise the mammaliananimal body, preferably the human body.

The present invention further relates to a pharmaceutical compositionfor the treatment or prevention of specific fibrotic diseases whichcomprises a compound of above general formula I alone or in combinationwith one or more further therapeutic agents.

BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWING

FIG. 1A depicts lung tissue removed from a rat from a control group ofthe experiment described in Example B1(A) which received saline andvehicle (0.1% Natrosol) instead of bleomycin intratracheally.

FIG. 1B depicts lung tissue removed from a rat from a group of theexperiment described in Example B1(A) which was treated intratracheallywith bleomycin and vehicle.

FIG. 1C depicts lung tissue removed from a rat from a group of theexperiment described in Example B1(A) which were treated with bleomycinand also treated with Compound (m).

FIGS. 2 and 3 depict the results experiments described in Example B1(B)to determine the effect of Compound (m) on expression of fibrotic markergenes (procollagen I and fibronectin, respectively) followingbleomycin-induced pulmonary fibrosis.

FIG. 4A depicts lung tissue removed from a rat from a control group ofthe experiment described in Example B2 which received saline and vehicle(0.1% Natrosol) instead of bleomycin intratracheally.

FIG. 4B depicts lung tissue removed from a rat from a group of theexperiment described in Example B2 which was treated intratracheallywith bleomycin and vehicle.

FIG. 4C depicts lung tissue removed from a rat from a group of theexperiment described in Example B2 which were treated with bleomycin andalso treated with Compound (u).

FIGS. 5 and 6 depict the results experiments described in Example B2 todetermine the effect of Compound (u) on expression of fibrotic markergenes (procollagen I and fibronectin, respectively) followingbleomycin-induced pulmonary fibrosis.

DETAILED DESCRIPTION OF THE INVENTION

In accordance with the present invention, the compounds of above generalformula I are the compounds

in which

X denotes an oxygen or sulphur atom,

R₁ denotes a hydrogen atom or a prodrug group such as aC₁₋₄-alkoxycarbonyl or C₂₋₄-alkanoyl group,

R₂ denotes a carboxy group, a straight-chain or branchedC₁₋₆-alkoxy-carbonyl group, a C₄₋₇-cycloalkoxy-carbonyl or anaryloxycarbonyl group,

a straight-chain or branched C₁₋₆-alkoxy-carbonyl group, which isterminally substituted in the alkyl moiety by a phenyl, heteroaryl,carboxy, C₁₋₃-alkoxy-carbonyl, aminocarbonyl, C₁₋₃-alkylamino-carbonylor di-(C₁₋₃-alkyl)-aminocarbonyl group,

a straight-chain or branched C₂₋₆-alkoxy-carbonyl group, which isterminally substituted in the alkyl moiety by a chlorine atom or ahydroxy, C₁₋₃-alkoxy, amino, C₁₋₃-alkylamino or di-(C₁₋₃-alkyl)-aminogroup,

an aminocarbonyl or methylaminocarbonyl group, an ethylaminocarbonylgroup optionally substituted in the 2 position of the ethyl group by ahydroxy or C₁₋₃-alkoxy group or a di-(C₁₋₂-alkyl)-aminocarbonyl group,

R₃ denotes a hydrogen atom, a C₁₋₆-alkyl, C₃₋₇-cycloalkyl,trifluoromethyl or heteroaryl group,

a phenyl or naphthyl group, a phenyl or naphthyl group mono- ordisubstituted by a fluorine, chlorine, bromine or iodine atom, by atrifluoromethyl, C₁₋₃-alkyl or C₁₋₃-alkoxy group, whilst in the event ofdisubstitution the substituents may be identical or different andwherein the abovementioned unsubstituted as well as the mono- anddisubstituted phenyl and naphthyl groups may additionally be substituted

by a hydroxy, hydroxy-C₁₋₃-alkyl or C₁₋₃-alkoxy-C₁₋₃-alkyl group,

by a cyano, carboxy, carboxy-C₁₋₃-alkyl, C₁₋₃-alkoxycarbonyl,aminocarbonyl, C₁₋₃-alkylamino-carbonyl or di-(C₁₋₃-alkyl)-aminocarbonylgroup,

by a nitro group,

by an amino, C₁₋₃-alkylamino, di-(C₁₋₃-alkyl)-amino or amino-C₁₋₃-alkylgroup,

by a C₁₋₃-alkylcarbonylamino, N—(C₁₋₃-alkyl)-C₁₋₃-alkylcarbonylamino,C₁₋₃-alkylcarbonylamino-C₁₋₃-alkyl,N—(C₁₋₃-alkyl)-C₁₋₃-alkylcarbonylamino-C₁₋₃-alkyl,C₁₋₃-alkylsulphonylamino, C₁₋₃-alkylsulphonylamino-C₁₋₃-alkyl,N—(C₁₋₃-alkyl)-C₁₋₃-alkylsulphonylamino-C₁₋₃-alkyl oraryl-C₁₋₃-alkylsulphonylamino group,

by a cycloalkylamino, cycloalkyleneimino, cycloalkyleneiminocarbonyl,cycloalkyleneimino-C₁₋₃-alkyl, cycloalkyleneiminocarbonyl-C₁₋₃-alkyl orcycloalkyleneiminosulphonyl-C₁₋₃-alkyl group having 4 to 7 ring membersin each case, whilst in each case the methylene group in position 4 of a6- or 7-membered cycloalkyleneimino group may be replaced by an oxygenor sulphur atom, by a sulphinyl, sulphonyl, —NH or —N(C₁₋₃-alkyl) group,

or by a heteroaryl or heteroaryl-C₁₋₃-alkyl group,

R₄ denotes a C₃₋₇-cycloalkyl group,

whilst the methylene group in the 4 position of a 6- or 7-memberedcycloalkyl group may be substituted by an amino, C₁₋₃-alkylamino ordi-(C₁₋₃-alkyl)-amino group or replaced by an —NH or —N(C₁₋₃-alkyl)group,

or a phenyl group substituted by the group R₆, which may additionally bemono- or disubstituted by fluorine, chlorine, bromine or iodine atoms,by C₁₋₅-alkyl, trifluoromethyl, hydroxy, C₁₋₃-alkoxy, carboxy,C₁₋₃-alkoxycarbonyl, amino, acetylamino, C₁₋₃-alkyl-sulphonyl-amino,aminocarbonyl, C₁₋₃-alkyl-aminocarbonyl, di-(C₁₋₃-alkyl)-aminocarbonyl,aminosulphonyl, C₁₋₃-alkyl-aminosulphonyl,di-(C₁₋₃-alkyl)-aminosulphonyl, nitro or cyano groups, wherein thesubstituents may be identical or different and wherein

R₆ denotes a hydrogen, fluorine, chlorine, bromine or iodine atom,

a cyano, nitro, amino, C₁₋₅-alkyl, C₃₋₇-cycloalkyl, trifluoromethyl,phenyl, tetrazolyl or heteroaryl group,

the group of formula

wherein the hydrogen atoms bound to a nitrogen atom may in each case bereplaced independently of one another by a C₁₋₃-alkyl group,

a C₁₋₃-alkoxy group, a C₁₋₃-alkoxy-C₁₋₃-alkoxy, phenyl-C₁₋₃-alkoxy,amino-C₂₋₃-alkoxy, C₁₋₃-alkylamino-C₂₋₃-alkoxy,di-(C₁₋₃-alkyl)-amino-C₂₋₃-alkoxy, phenyl-C₁₋₃-alkylamino-C₂₋₃-alkoxy,N—(C₁₋₃-alkyl)-phenyl-C₁₋₃-alkylamino-C₂₋₃-alkoxy,C₅₋₇-cycloalkyleneimino-C₂₋₃-alkoxy or C₁₋₃-alkylmercapto group,

a carboxy, C₁₋₄-alkoxycarbonyl, aminocarbonyl, C₁₋₃-alkyl-aminocarbonyl,N—(C₁₋₅-alkyl)-C₁₋₃-alkylaminocarbonyl, phenyl-C₁₋₃-alkylamino-carbonyl,N—(C₁₋₃-alkyl)-phenyl-C₁₋₃-alkylamino-carbonyl, piperazinocarbonyl orN—(C₁₋₃-alkyl)-piperazinocarbonyl group,

a C₁₋₃-alkylaminocarbonyl or N—(C₁₋₅-alkyl)-C₁₋₃-alkylaminocarbonylgroup wherein an alkyl moiety is substituted by a carboxy orC₁₋₃-alkoxycarbonyl group or in the 2 or 3 position by adi-(C₁₋₃-alkyl)-amino, piperazino, N—(C₁₋₃-alkyl)-piperazino or a 4- to7-membered cycloalkyleneimino group,

a C₃₋₇-cycloalkyl-carbonyl group,

wherein the methylene group in the 4 position of the 6- or 7-memberedcycloalkyl moiety may be substituted by an amino, C₁₋₃-alkylamino ordi-(C₁₋₃-alkyl)-amino group or replaced by an —NH or —N(C₁₋₃-alkyl)group,

a 4- to 7-membered cycloalkyleneimino group wherein

a methylene group linked to the imino group may be replaced by acarbonyl or sulphonyl group or

the cycloalkylene moiety may be fused to a phenyl ring or one or twohydrogen atoms may each be replaced by a C₁₋₃-alkyl group and/or

in each case the methylene group in the 4 position of a 6- or 7-memberedcycloalkyleneimino group may be substituted by a carboxy,C₁₋₃-alkoxycarbonyl, aminocarbonyl, C₁₋₃-alkylaminocarbonyl,di-(C₁₋₃-alkyl)-aminocarbonyl, phenyl-C₁₋₃-alkylamino orN—(C₁₋₃-alkyl)-phenyl-C₁₋₃-alkylamino group or

may be replaced by an oxygen or sulphur atom, by a sulphinyl,

sulphonyl, —NH, —N(C₁₋₃-alkyl), —N(phenyl), —N(C₁₋₃-alkyl-carbonyl) or—N(benzoyl) group,

a C₁₋₄-alkyl group substituted by the group R₇, wherein

R₇ denotes a C₃₋₇-cycloalkyl group,

whilst the methylene group in the 4 position of a 6- or 7-memberedcycloalkyl group may be substituted by an amino, C₁₋₃-alkylamino ordi-(C₁₋₃-alkyl)-amino group or replaced by an —NH or —N(C₁₋₃-alkyl)group or

in a 5- to 7-membered cycloalkyl group a —(CH₂)₂ group may be replacedby a —CO—NH group, a —(CH₂)₃ group may be replaced by a —NH—CO—NH or—CO—NH—CO group or a —(CH₂)₄ group may be replaced by a —NH—CO—NH—COgroup, whilst in each case a hydrogen atom bound to a nitrogen atom maybe replaced by a C₁₋₃-alkyl group,

an aryl or heteroaryl group,

a hydroxy or C₁₋₃-alkoxy group, an amino, C₁₋₇-alkylamino,di-(C₁₋₇-alkyl)-amino, phenylamino, N-phenyl-C₁₋₃-alkyl-amino,phenyl-C₁₋₃-alkylamino, N—(C₁₋₃-alkyl)-phenyl-C₁₋₃-alkylamino ordi-(phenyl-C₁₋₃-alkyl)-amino group, an ω-hydroxy-C₂₋₃-alkyl-amino,N—(C₁₋₃-alkyl)-ω-hydroxy-C₂₋₃-alkyl-amino,di-(ω-hydroxy-C₂₋₃-alkyl)-amino, di-(ω—(C₁₋₃-alkoxy)-C₂₋₃-alkyl)-aminoor N-(dioxolan-2-yl)-C₁₋₃-alkyl-amino group,

a C₁₋₃-alkylcarbonylamino-C₂₋₃-alkyl-amino orC₁₋₃-alkylcarbonylamino-C₂₋₃-alkyl-N—(C₁₋₃-alkyl)-amino group,

a C₁₋₃-alkylsulphonylamino, N—(C₁₋₃-alkyl)-C₁₋₃-alkylsulphonylamino,C₁₋₃-alkylsulphonylamino-C₂₋₃-alkyl-amino orC₁₋₃-alkylsulphonylamino-C₂₋₃-alkyl-N—(C₁₋₃-alkyl)-amino group,

a hydroxycarbonyl-C₁₋₃-alkylamino orN—(C₁₋₃-alkyl)-hydroxycarbonyl-C₁₋₃-alkyl-amino group,

a guanidino group wherein one or two hydrogen atoms may each be replacedby a C₁₋₃-alkyl group,

a group of formula

—N(R₈)—CO—(CH₂)_(n)—R₉  (II),

wherein

R₈ denotes a hydrogen atom or a C₁₋₃-alkyl group,

n denotes one of the numbers 0, 1, 2 or 3 and

R₉ denotes an amino, C₁₋₄-alkylamino, di-(C₁₋₄-alkyl)-amino,phenylamino, N—(C₁₋₄-alkyl)-phenylamino, benzylamino,N—(C₁₋₄-alkyl)-benzylamino or C₁₋₄-alkoxy group, a 4- to 7-memberedcycloalkyleneimino group, whilst in each case the methylene group in the4 position of a 6- or 7-membered cycloalkyleneimino group may bereplaced by an oxygen or sulphur atom, by a sulphinyl, sulphonyl, —NH,—N(C₁₋₃-alkyl), —N(phenyl), —N(C₁₋₃-alkyl-carbonyl) or —N(benzoyl)group, or, if n denotes one of the numbers 1, 2 or 3, it may also denotea hydrogen atom, a group of formula

—N(R₁₀)—(CH₂)_(m)—(CO)_(o)—R₁₁  (III),

wherein

R₁₀ denotes a hydrogen atom, a C₁₋₃-alkyl group, a C₁₋₃-alkylcarbonyl,arylcarbonyl, phenyl-C₁₋₃-alkyl-carbonyl, C₁₋₃-alkylsulphonyl,arylsulphonyl or phenyl-C₁₋₃-alkylsulphonyl group,

m denotes one of the numbers 1, 2, 3 or 4,

o denotes the number 1 or, if m denotes one of the numbers 2, 3 or 4, omay also denote the number 0 and

R₁₁ denotes an amino, C₁₋₄-alkylamino, di-(C₁₋₄-alkyl)-amino,phenylamino, N—(C₁₋₄-alkyl)-phenylamino, benzylamino,N—(C₁₋₄-alkyl)-benzylamino, C₁₋₄-alkoxy or C₁₋₃-alkoxy-C₁₋₃-alkoxygroup, a di-(C₁₋₄-alkyl)-amino-C₁₋₃-alkylamino group optionallysubstituted in the 1 position by a C₁₋₃-alkyl group or a 4- to7-membered cycloalkyleneimino group, wherein the cycloalkylene moietymay be fused to a phenyl ring or in each case the methylene group in the4 position of a 6- or 7-membered cycloalkyleneimino group may bereplaced by an oxygen or sulphur atom, by a sulphinyl, sulphonyl, —NH,—N(C₁₋₃-alkyl), —N(phenyl), —N(C₁₋₃-alkyl-carbonyl) or —N(benzoyl)group,

a C₄₋₇-cycloalkylamino, C₄₋₇-cycloalkyl-C₁₋₃-alkylamino orC₄₋₇-cycloalkenylamino group wherein position 1 of the ring is notinvolved in the double bond and wherein the abovementioned groups mayeach additionally be substituted at the amino-nitrogen atom by aC₅₋₇-cycloalkyl, C₂₋₄-alkenyl or C₁₋₄-alkyl group,

a 4- to 7-membered cycloalkyleneimino group, wherein

the cycloalkylene moiety may be fused to a phenyl group or to anoxazolo, imidazolo, thiazolo, pyridino, pyrazino or pyrimidino groupoptionally substituted by a fluorine, chlorine, bromine or iodine atom,by a nitro, C₁₋₃-alkyl, C₁₋₃-alkoxy or amino group, and/or

one or two hydrogen atoms may each be replaced by a C₁₋₃-alkyl,C₅₋₇-cycloalkyl or phenyl group and/or

the methylene group in the 3 position of a 5-membered cycloalkyleneiminogroup may be substituted by a hydroxy, hydroxy-C₁₋₃-alkyl, C₁₋₃-alkoxyor C₁₋₃-alkoxy-C₁₋₃-alkyl group,

the methylene group in the 3 or 4 position of a 6- or 7-memberedcycloalkyleneimino group may in each case be substituted by a hydroxy,hydroxy-C₁₋₃-alkyl, C₁₋₃-alkoxy, C₁₋₃-alkoxy-C₁₋₃-alkyl, carboxy,C₁₋₄-alkoxycarbonyl, aminocarbonyl, C₁₋₃-alkylaminocarbonyl,di-(C₁₋₃-alkyl)-aminocarbonyl, phenyl-C₁₋₃-alkylamino orN—(C₁₋₃-alkyl)-phenyl-C₁₋₃-alkyl-amino group or

may be replaced by an oxygen or sulphur atom, by a sulphinyl, sulphonyl,—NH, —N(C₁₋₃-alkyl-), —N(phenyl), —N(phenyl-C₁₋₃-alkyl-),—N(C₁₋₃-alkyl-carbonyl-), —N(C₁₋₄-alkyl-hydroxy-carbonyl-),—N(C₁₋₄-alkoxy-carbonyl-), —N(benzoyl-) or—N(phenyl-C₁₋₃-alkyl-carbonyl-) group,

wherein a methylene group linked to an imino-nitrogen atom of thecycloalkyleneimino group may be replaced by a carbonyl or sulphonylgroup or in a 5- to 7-membered monocyclic cycloalkyleneimino group or acycloalkyleneimino group fused to a phenyl group the two methylenegroups linked to the imino-nitrogen atom may each be replaced by acarbonyl group,

or R₆ denotes a C₁₋₄-alkyl group which is substituted by a carboxy,C₁₋₃-alkoxycarbonyl, aminocarbonyl, C₁₋₃-alkylaminocarbonyl ordi-(C₁₋₃-alkyl)-aminocarbonyl group or by a 4- to 7-memberedcycloalkyleneiminocarbonyl group,

an N—(C₁₋₃-alkyl)-C₂₋₄-alkanoylamino group which is additionallysubstituted in the alkyl moiety by a carboxy or C₁₋₃-alkoxycarbonylgroup,

a group of formula

—N(R₁₂)—CO—(CH₂)_(p)—R₁₃  (IV),

wherein

R₁₂ denotes a hydrogen atom, a C₁₋₆-alkyl or C₃₋₇-cycloalkyl group or aC₁₋₃-alkyl group terminally substituted by a phenyl, heteroaryl,trifluoromethyl, hydroxy, C₁₋₃-alkoxy, aminocarbonyl,C₁₋₄-alkylamino-carbonyl, di-(C₁₋₄-alkyl)-aminocarbonyl,C₁₋₃-alkyl-carbonyl, C₁₋₃-alkyl-sulphonyl-amino,N—(C₁₋₃-alkyl)-C₁₋₃-alkyl-sulphonylamino, C₁₋₃-alkyl-aminosulphonyl ordi-(C₁₋₃-alkyl)-aminosulphonyl group and

p denotes one of the numbers 0, 1, 2 or 3 and

R₁₃ assumes the meanings of the abovementioned group R₇, or, if pdenotes one of the numbers 1, 2 or 3, it may also denote a hydrogenatom,

a group of formula

—N(R₁₄)—(CH₂)_(q)—(CO)_(r)—R₁₅  (V),

wherein

R₁₄ denotes a hydrogen atom, a C₁₋₄-alkyl group, a C₁₋₃-alkylcarbonyl,arylcarbonyl, phenyl-C₁₋₃-alkylcarbonyl, heteroarylcarbonyl,heteroaryl-C₁₋₃-alkylcarbonyl, C₁₋₄-alkylsulphonyl, arylsulphonyl,phenyl-C₁₃-alkylsulphonyl, heteroarylsulphonyl orheteroaryl-C₁₃-alkyl-sulphonyl group,

q denotes one of the numbers 1, 2, 3 or 4,

r denotes the number 1 or, if q is one of the numbers 2, 3 or 4, it mayalso denote the number 0 and

R₁₅ assumes the meanings of the abovementioned group R₇, a group offormula

—N(R₁₆)—SO₂—R₁₇  (VI),

wherein

R₁₆ denotes a hydrogen atom or a C₁₋₄-alkyl group optionally terminallysubstituted by a cyano, trifluoromethyl-carbonylamino orN—(C₁₋₃-alkyl)-trifluoromethyl-carbonyl-amino group and

R₁₇ denotes a C₁₋₃-alkyl group, an amino group substituted by adi-(C₁₋₃-alkyl)-amino-C₁₋₃-alkyl-carbonyl ordi-(C₁₋₃-alkyl)-amino-C₁₋₃-alkyl-sulphonyl group and adi-(C₁₋₃-alkyl)-aminocarbonyl-C₁₋₃-alkyl group,

or an N—(C₁₋₃-alkyl)-C₁₋₅-alkylsulphonylamino orN—(C₁₋₃-alkyl)-phenylsulphonylamino group wherein the alkyl moiety isadditionally substituted by a cyano or carboxy group,

wherein all the single-bonded or fused phenyl groups contained in thegroups mentioned under R₆ may be mono- or disubstituted by fluorine,chlorine, bromine or iodine atoms, by C₁₋₅-alkyl, trifluoromethyl,hydroxy, C₁₋₃-alkoxy, carboxy, C₁₋₃-alkoxycarbonyl, aminocarbonyl,C₁₋₄-alkylamino-carbonyl, di-(C₁₋₄-alkyl)-amino-carbonyl,aminosulphonyl, C₁₋₃-alkyl-aminosulphonyl,di-(C₁₋₃-alkyl)-aminosulphonyl, C₁₋₃-alkyl-sulphonylamino, nitro orcyano groups, wherein the substituents may be identical or different, ortwo adjacent hydrogen atoms of the phenyl groups may be replaced by amethylenedioxy group,

and

R₅ denotes a hydrogen atom or a C₁₋₃-alkyl group,

wherein by an aryl group is meant a phenyl or naphthyl group optionallymono- or disubstituted by a fluorine, chlorine, bromine or iodine atom,by a cyano, trifluoromethyl, nitro, carboxy, aminocarbonyl, C₁₋₃-alkylor C₁₋₃-alkoxy group and

by a heteroaryl group is meant a monocyclic 5- or 6-membered heteroarylgroup optionally substituted by a C₁₋₃-alkyl group in the carbonskeleton, wherein

the 6-membered heteroaryl group contains one, two or three nitrogenatoms and

the 5-membered heteroaryl group contains an imino group optionallysubstituted by a C₁₋₃-alkyl or phenyl-C₁₋₃-alkyl group, an oxygen orsulphur atom or

an imino group optionally substituted by a C₁₋₃-alkyl orphenyl-C₁₋₃-alkyl group or an oxygen or sulphur atom and additionally anitrogen atom or

an imino group optionally substituted by a C₁₋₃-alkyl orphenyl-C₁₋₃-alkyl group and two nitrogen atoms,

and moreover a phenyl ring may be fused to the abovementioned monocyclicheterocyclic groups via two adjacent carbon atoms and the bonding takesplace via a nitrogen atom or via a carbon atom of the heterocyclicmoiety or a fused phenyl ring,

some or all of the hydrogen atoms in the abovementioned alkyl and alkoxygroups or in the alkyl moieties contained in the above-defined groups offormula I optionally being replaced by fluorine atoms,

the saturated alkyl and alkoxy moieties with more than 2 carbon atomswhich are present in the groups defined hereinbefore also include thebranched isomers thereof, such as for example the isopropyl, tert.butyl,isobutyl group, unless otherwise stated, and

additionally the hydrogen atom of any carboxy group present or ahydrogen atom bound to a nitrogen atom, e.g. a hydrogen atom of anamino, alkylamino or imino group or a saturated N-heterocycle such asthe piperidinyl group, may each be replaced by a group which can becleaved in vivo.

By a group which can be cleaved in vivo from an imino or amino group ismeant, for example, a hydroxy group, an acyl group such as the benzoylor pyridinoyl group or a C₁₋₁₆-alkanoyl group such as the formyl,acetyl, propionyl, butanoyl, pentanoyl or hexanoyl group, anallyloxycarbonyl group, a C₁₋₁₆-alkoxycarbonyl group such as themethoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl,butoxycarbonyl, tert.butoxycarbonyl, pentoxycarbonyl, hexyloxycarbonyl,octyloxycarbonyl, nonyloxycarbonyl, decyloxycarbonyl,undecyloxycarbonyl, dodecyloxycarbonyl or hexadecyloxycarbonyl group, aphenyl-C₁₋₆-alkoxycarbonyl group such as the benzyloxycarbonyl,phenylethoxycarbonyl or phenylpropoxycarbonyl group, aC₁₋₃-alkylsulphonyl-C₂₋₄-alkoxycarbonyl,C₁₋₃-alkoxy-C₂₋₄-alkoxy-C₂₋₄-alkoxycarbonyl orR_(e)CO—O—(R_(f)CR_(g))—O—CO group wherein

R_(e) denotes a C₁₋₈-alkyl, C₅₋₇-cycloalkyl, phenyl or phenyl-C₁₋₃-alkylgroup,

R_(f) denotes a hydrogen atom, a C₁₋₃-alkyl, C₅₋₇-cycloalkyl or phenylgroup and

R_(g) denotes a hydrogen atom, a C₁₋₃-alkyl or R_(e)CO—O—(R_(f)CR_(g))—Ogroup wherein R_(e) to R_(g) are as hereinbefore defined,

wherein additionally the amino group may be a phthalimido group, whilstthe abovementioned ester groups may also be used as a group which can beconverted in vivo into a carboxy group.

One sub-group of compounds of general formula I which deserves specialmention comprises those wherein

X, R₁ and R₃ to R₅ are as hereinbefore defined and

R₂ denotes a straight-chain or branched C₁₋₆-alkoxy-carbonyl group, aC₄₋₇-cycloalkoxycarbonyl or a aryloxycarbonyl group,

a straight-chain or branched C₁₋₆-alkoxy-carbonyl group, which isterminally substituted in the alkyl moiety by a phenyl, heteroaryl,carboxy, C₁₋₃-alkoxycarbonyl, aminocarbonyl, C₁₋₃-alkylaminocarbonyl ordi-(C₁₋₃-alkyl)-aminocarbonyl group,

a straight-chain or branched C₂₋₆-alkoxy-carbonyl group, which isterminally substituted in the alkyl moiety by a chlorine atom or ahydroxy, C₁₋₃-alkoxy, amino, C₁₋₃-alkylamino or di-(C₁₋₃-alkyl)-aminogroup,

the tautomers, the diastereomers, the enantiomers, the mixtures thereofand the salts thereof.

A second sub-group of compounds of general formula I which deservesspecial mention comprises those wherein

X, R₁ and R₃ to R₅ are as hereinbefore defined and

R₂ denotes an aminocarbonyl or methylaminocarbonyl group, anethylaminocarbonyl group optionally substituted in the 2 position of theethyl group by a hydroxy or C₁₋₃-alkoxy group or adi-(C₁₋₂-alkyl)-aminocarbonyl group,

the tautomers, the diastereomers, the enantiomers, the mixtures thereofand the salts thereof.

A third sub-group of compounds of general formula I which deservesspecial mention comprises those wherein

X, R₁ to R₃ and R₅ are as hereinbefore defined and

R₄ denotes an R₇—(C₁₋₄-alkyl)-phenyl group, wherein

R₇ denotes an amino, C₁₋₇-alkylamino, di-(C₁₋₇-alkyl)-amino,phenylamino, N-phenyl-C₁₋₃-alkyl-amino, phenyl-C₁₋₃-alkyl-amino,N—(C₁₋₃-alkyl)-phenyl-C₁₋₃-alkylamino or di-(phenyl-C₁₋₃-alkyl)-aminogroup,

or a phenyl group substituted by the group of formula

—N(R₁₂)—CO—(CH₂)_(p)—R₁₃  (IV),

wherein R₁₂, p and R₁₃ are as hereinbefore defined,

the tautomers, the diastereomers, the enantiomers, the mixtures thereofand the salts thereof.

Preferred compounds of general formula I are those wherein

R₁ and R₃ are as hereinbefore defined and

X denotes an oxygen atom,

R₂ denotes a carboxy group, a straight-chain or branchedC₁₋₆-alkoxy-carbonyl group, a C₅₋₇-cycloalkoxycarbonyl or aphenoxycarbonyl group,

a straight-chain or branched C₁₋₃-alkoxy-carbonyl group, which isterminally substituted in the alkyl moiety by a phenyl, heteroaryl,carboxy, C₁₋₃-alkoxycarbonyl, aminocarbonyl, C₁₋₃-alkylaminocarbonyl ordi-(C₁₋₃-alkyl)-aminocarbonyl group,

a straight-chain or branched C₂₋₃-alkoxy-carbonyl group, which isterminally substituted in the alkyl moiety by a chlorine atom, by ahydroxy, C₁₋₃-alkoxy, amino, C₁₋₃-alkylamino or di-(C₁₋₃-alkyl)-aminogroup,

an aminocarbonyl or methylaminocarbonyl group, an ethylaminocarbonylgroup optionally substituted in the 2 position of the ethyl group by ahydroxy or C₁₋₃-alkoxy group or a di-(C₁₋₂-alkyl)-aminocarbonyl group,

R₄ denotes a C₃₋₇-cycloalkyl group,

whilst the methylene group in the 4 position of a 6- or 7-memberedcycloalkyl group may be substituted by an amino, C₁₋₃-alkylamino ordi-(C₁₋₃-alkyl)-amino group or replaced by an —NH or —N(C₁₋₃-alkyl)group,

or a phenyl group substituted by the group R₆, which may additionally bemono- or disubstituted by fluorine, chlorine or bromine atoms, byC₁₋₃-alkyl, trifluoromethyl, hydroxy, C₁₋₃-alkoxy, carboxy,C₁₋₃-alkoxycarbonyl, amino, acetylamino, aminocarbonyl,C₁₋₃-alkyl-aminocarbonyl, di-(C₁₋₃-alkyl)-aminocarbonyl, nitro or cyanogroups, wherein the substituents may be identical or different andwherein

R₆ denotes a hydrogen, fluorine, chlorine, bromine or iodine atom,

a cyano, nitro, amino, C₁₋₅-alkyl, C₃₋₇-cycloalkyl, trifluoromethyl,phenyl, tetrazolyl or heteroaryl group,

the group of formula

wherein a hydrogen atom bound to the nitrogen atom may be replaced by aC₁₋₃-alkyl group,

a C₁₋₃-alkoxy group, an amino-C₂₋₃-alkoxy, C₁₋₃-alkylamino-C₂₋₃-alkoxy,di-(C₁₋₃-alkyl)-amino-C₂₋₃-alkoxy, phenyl-C₁₋₃-alkylamino-C₂₋₃-alkoxy,N—(C₁₋₃-alkyl)-phenyl-C₁₋₃-alkylamino-C₂₋₃-alkoxy,pyrrolidino-C₂₋₃-alkoxy, piperidino-C₂₋₃-alkoxy or C₁₋₃-alkylmercaptogroup, a carboxy, C₁₋₄-alkoxycarbonyl, aminocarbonyl,C₁₋₃-alkyl-amino-carbonyl, phenyl-C₁₋₃-alkylamino-carbonyl orN—(C₁₋₃-alkyl)-phenyl-C₁₋₃-alkylamino-carbonyl group,

a C₃₋₇-cycloalkyl-carbonyl group,

wherein the methylene group in the 4 position of the 6- or 7-memberedcycloalkyl moiety may be replaced by an —NH or —N(C₁₋₃-alkyl) group,

a 4- to 7-membered cycloalkyleneimino group, wherein

a methylene group linked to the imino group may be replaced by acarbonyl or sulphonyl group or

one or two hydrogen atoms may each be replaced by a C₁₋₃-alkyl groupand/or

in each case the methylene group in the 4 position of a 6- or 7-memberedcycloalkyleneimino group may be substituted by a carboxy,C₁₋₃-alkoxycarbonyl, aminocarbonyl, C₁₋₃-alkylaminocarbonyl,di-(C₁₋₃-alkyl)-aminocarbonyl, phenyl-C₁₋₃-alkylamino orN—(C₁₋₃-alkyl)-phenyl-C₁₋₃-alkylamino group or

may be replaced by an oxygen or sulphur atom, by a sulphinyl, sulphonyl,—NH or —N(C₁₋₃-alkyl) group,

a C₁₋₄-alkyl group terminally substituted by the group R₇, wherein

R₇ denotes a C₅₋₇-cycloalkyl group,

whilst the methylene group in the 4 position of a 6- or 7-memberedcycloalkyl group may be replaced by an —NH or —N(C₁₋₃-alkyl) group or ina 5- to 7-membered cycloalkyl group a —(CH₂)₂ group may be replaced by a—CO—NH group, a —(CH₂)₃ group may be replaced by a —NH—CO—NH— or a—(CH₂)₄ group may be replaced by a —NH—CO—NH—CO group, whilst in eachcase a hydrogen atom bound to a nitrogen atom may be replaced by aC₁₋₃-alkyl group,

a phenyl or heteroaryl group,

a hydroxy or C₁₋₃-alkoxy group, an amino, C₁₋₆-alkylamino,di-(C₁₋₆-alkyl)-amino, phenylamino, N-phenyl-C₁₋₃-alkyl-amino,phenyl-C₁₋₃-alkylamino, N—(C₁₋₃-alkyl)-phenyl-C₁₋₃-alkylamino ordi-(phenyl-C₁₋₃-alkyl)-amino group,

a ω-hydroxy-C₂₋₃-alkyl-amino, N—(C₁₋₃-alkyl)-ω-hydroxy-—C₂₋₃-alkyl-amino, di-(ω-hydroxy-C₂₋₃-alkyl)-amino,di-(ω—(C₁₋₃-alkoxy)-C₂₋₃-alkyl)-amino orN-(dioxolan-2-yl)-C₁₋₃-alkyl-amino group,

a C₁₋₃-alkylcarbonylamino-C₂₋₃-alkyl-amino orC₁₋₃-alkylcarbonylamino-C₂₋₃-alkyl-N—(C₁₋₃-alkyl)-amino group,

a C₁₋₃-alkylsulphonylamino, N—(C₁₋₃-alkyl)-C₁₋₃-alkylsulphonylamino,C₁₋₃-alkylsulphonylamino- —C₂₋₃-alkyl-amino orC₁₋₃-alkylsulphonylamino-C₂₋₃-alkyl- —N—(C₁₋₃-alkyl)-amino group,

a hydroxycarbonyl-C₁₋₃-alkylamino orN—(C₁₋₃-alkyl)-hydroxycarbonyl-C₁₋₃-alkyl-amino group

a guanidino group wherein a hydrogen atom may be replaced by aC₁₋₃-alkyl group,

a group of formula

—N(R₈)—CO—(CH₂)_(n)—R₉  (II),

wherein

R₈ denotes a hydrogen atom or a C₁₋₃-alkyl group,

n denotes one of the numbers 0, 1, 2 or 3 and

R₉ denotes an amino, C₁₋₃-alkylamino, di-(C₁₋₃-alkyl)-amino,phenylamino, benzylamino or C₁₋₄-alkoxy group, a 5- to 7-memberedcycloalkyleneimino group, wherein the methylene group in position 4 ofthe piperidino group may be replaced by an oxygen or sulphur atom, by

an —NH, —N(C₁₋₃-alkyl), —N(phenyl), —N(C₁₋₃-alkyl-carbonyl) or—N(benzoyl) group, or, if n denotes one of the numbers 1, 2 or 3, it mayalso denote a hydrogen atom,

a group of formula

—N(R₁₀)—(CH₂)_(m)—(CO)_(o)—R₁₁  (III),

wherein

R₁₀ denotes a hydrogen atom, a C₁₋₃-alkyl group, a C₁₋₃-alkylcarbonyl orC₁₋₃-alkylsulphonyl group,

m denotes one of the numbers 1, 2 or 3,

o denotes the number 1 or, if m is one of the numbers 2 or 3, o may alsodenote the number 0 and

R₁₁ denotes an amino, C₁₋₃-alkylamino, di-(C₁₋₃-alkyl)-amino,C₁₋₄-alkoxy or C₁₋₃-alkoxy-C₁₋₃-alkoxy group or a 5- to 7-memberedcycloalkyleneimino group, wherein the methylene group in position 4 ofthe piperidino group may be replaced by an oxygen or sulphur atom, by an—NH, —N(C₁₋₃-alkyl), —N(phenyl), —N(C₁₋₃-alkyl-carbonyl) or —N(benzoyl)group,

a C₄₋₇-cycloalkylamino or C₄₋₇-cycloalkenylamino group wherein position1 of the ring is not involved in the double bond,

a 4- to 7-membered cycloalkyleneimino group, wherein

the cycloalkylene moiety may be fused to a phenyl group or

one or two hydrogen atoms may each be replaced by a C₁₋₃-alkyl groupand/or

the methylene group in position 3 of the pyrrolidino group may besubstituted by a hydroxy or C₁₋₃-alkoxy group,

in each case the methylene group in the 4 position of a 6- or 7-memberedcycloalkyleneimino group may be substituted by a hydroxy,hydroxy-C₁₋₃-alkyl, C₁₋₃-alkoxy, carboxy, C₁₋₃-alkoxycarbonyl,aminocarbonyl, C₁₋₃-alkylaminocarbonyl, di-(C₁₋₃-alkyl)-aminocarbonyl,phenyl-C₁₋₃-alkylamino or N—(C₁₋₃-alkyl)-phenyl-C₁₋₃-alkylamino group or

may be replaced by an oxygen or sulphur atom, by a sulphinyl,

sulphonyl, —NH, —N(C₁₋₃-alkyl), —N(phenyl), —N(phenyl-C₁₋₃-alkyl),—N(C₁₋₃-alkyl-carbonyl), —N(C₁₋₄-alkoxy-carbonyl), —N(benzoyl) or—N(phenyl-C₁₋₃-alkyl-carbonyl) group,

wherein a methylene group linked to an imino-nitrogen atom of thecycloalkyleneimino group may be replaced by a carbonyl or sulphonylgroup or in a 5- to 6-membered monocyclic cycloalkyleneimino group or acycloalkyleneimino group fused to a phenyl group the two methylenegroups linked to the imino-nitrogen atom may each be replaced by acarbonyl group,

or R₆ denotes a C₁₋₄-alkyl group which is terminally substituted by acarboxy, C₁₋₃-alkoxycarbonyl, aminocarbonyl, C₁₋₃-alkylaminocarbonyl ordi-(C₁₋₃-alkyl)-aminocarbonyl group or by a 4- to 7-memberedcycloalkyleneiminocarbonyl group,

a group of formula

—N(R₁₂)—CO—(CH₂)_(p)—R₁₃  (IV),

wherein

R₁₂ denotes a hydrogen atom, a C₁₋₃-alkyl, C₅₋₇-cycloalkyl,phenyl-C₁₋₃-alkyl or heteroaryl-C₁₋₃-alkyl group and

p denotes one of the numbers 0, 1, 2 or 3 and

R₁₃ assumes the meanings of the abovementioned group R₇, or, if pdenotes one of the numbers 1, 2 or 3, it may also denote a hydrogenatom,

a group of formula

—N(R₁₄)—(CH₂)_(q)—(CO)_(r)—R₁₅  (V),

wherein

R₁₄ denotes a hydrogen atom, a C₁₋₄-alkyl group, a C₁₋₃-alkylcarbonyl,phenylcarbonyl, phenyl-C₁₋₃-alkylcarbonyl, heteroarylcarbonyl,heteroaryl-C₁₋₃-alkylcarbonyl, C₁₋₄-alkylsulphonyl, phenylsulphonyl,phenyl-C₁₋₃-alkyl-sulphonyl-heteroarylsulphonyl orheteroaryl-C₁₋₃-alkyl-sulphonyl group,

q denotes one of the numbers 1, 2, 3 or 4,

r denotes the number 1 or, if q is one of the numbers 2, 3 or 4, it mayalso denote the number 0 and

R₁₅ assumes the meanings of the abovementioned group R₇,

a group of formula

—N(R₁₆)—SO₂—R₁₇  (VI),

wherein

R₁₆ denotes a hydrogen atom or a C₁₋₄-alkyl group optionally terminallysubstituted by a cyano, trifluoromethyl-carbonylamino orN—(C₁₋₃-alkyl)-trifluoromethyl- -carbonyl-amino group and

R₁₇ denotes a C₁₋₃-alkyl group,

an amino group substituted by adi-(C₁₋₃-alkyl)-amino-C₁₋₃-alkyl-carbonyl ordi-(C₁₋₃-alkyl)-amino-C₁₋₃-alkyl-sulphonyl group and adi-(C₁₋₃-alkyl)-aminocarbonyl-C₁₋₃-alkyl group,

wherein all the single-bonded or fused phenyl groups contained in thegroups mentioned under R₆ may be mono- or disubstituted by fluorine,chlorine or bromine atoms, by C₁₋₃-alkyl, trifluoromethyl, hydroxy,C₁₋₃-alkoxy, carboxy, C₁₋₃-alkoxycarbonyl, aminocarbonyl,C₁₋₃-alkyl-aminocarbonyl, aminosulphonyl, C₁₋₃-alkyl-aminosulphonyl,nitro or cyano groups, wherein the substituents may be identical ordifferent, or two adjacent hydrogen atoms of the phenyl groups may bereplaced by a methylenedioxy group, and

R₅ denotes a hydrogen atom or a C₁₋₃-alkyl group,

whilst by a heteroaryl group as mentioned above is meant a pyridinyl,pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, furyl, thienyl, oxazolyl,thiazolyl, pyrazolyl, imidazolyl or triazolyl group optionallysubstituted in the carbon skeleton by a C₁₋₃-alkyl group wherein ahydrogen atom bound to a nitrogen atom may be replaced by a C₁₋₃-alkylor phenyl-C₁₋₃-alkyl group and wherein the 5-membered heteroaryl groupscontaining at least one imino group are bound via a carbon or nitrogenatom,

a hydrogen atom bound to a nitrogen atom in the abovementioned groupsmay be replaced by a group which can be cleaved in vivo, particularly byan acetyl or tert.butoxycarbonyl group,

the carboxy groups contained in the abovementioned groups may each besubstituted by a group which can be cleaved in vivo and may occur, forexample, in the form of the tert.butoxycarbonyl group,

some or all of the hydrogen atoms in the abovementioned alkyl and alkoxygroups or in the alkyl moieties contained in the above-defined groups offormula I optionally being replaced by fluorine atoms and

the saturated alkyl and alkoxy moieties contained in the abovementionedgroups, which contain more than 2 carbon atoms, may be straight-chain orbranched, unless otherwise stated,

the tautomers, the diastereomers, the enantiomers, the mixtures thereofand the salts thereof.

One subgroup of preferred compounds of general formula I deservingspecial mention comprises those wherein

X, R₁ and R₃ to R₅ are as hereinbefore defined and

R₂ denotes a straight-chain or branched C₁₋₆-alkoxy-carbonyl group, aC₅₋₇-cycloalkoxycarbonyl or a phenoxycarbonyl group,

a straight-chain or branched C₁₋₃-alkoxy-carbonyl group, which isterminally substituted in the alkyl moiety by a phenyl- carboxy,C₁₋₃-alkoxycarbonyl, aminocarbonyl, C₁₋₃-alkylaminocarbonyl ordi-(C₁₋₃-alkyl)-aminocarbonyl group,

a straight-chain or branched C₂₋₃-alkoxy-carbonyl group, which isterminally substituted in the alkyl moiety by a hydroxy, C₁₋₃-alkoxy,amino, C₁₋₃-alkylamino or di-(C₁₋₃-alkyl)-amino group,

the tautomers, the diastereomers, the enantiomers, the mixtures thereofand the salts thereof.

A second sub-group of preferred compounds of general formula I deservingspecial mention comprises those wherein

X, R₁ and R₃ to R₅ are as hereinbefore defined and

R₂ denotes an aminocarbonyl or methylaminocarbonyl group, anethylaminocarbonyl group optionally substituted in the 2 position of theethyl group by a hydroxy or C₁₋₃-alkoxy group or adi-(C₁₋₂-alkyl)-aminocarbonyl group,

the tautomers, the diastereomers, the enantiomers, the mixtures thereofand the salts thereof.

A third sub-group of preferred compounds of general formula I deservingspecial mention comprises those wherein

X, R₁ to R₃ and R₅ are as hereinbefore defined and

R₄ denotes an R₇-(n-C₁₋₄-alkyl)-phenyl group, wherein

R₇ denotes an amino, C₁₋₆-alkylamino, di-(C₁₋₆-alkyl)-amino,phenylamino, N-phenyl-C₁₋₃-alkyl-amino, phenyl-C₁₋₃-alkyl-amino,N—(C₁₋₃-alkyl)-phenyl-C₁₋₃-alkylamino or di-(phenyl-C₁₋₃-alkyl)-aminogroup,

or a phenyl group substituted by the group of formula

—N(R₁₂)—CO—(CH₂)_(p)—R₁₃  (IV),

wherein R₁₂, p and R₁₃ are as hereinbefore defined,

the tautomers, the diastereomers, the enantiomers, the mixtures thereofand the salts thereof.

Particularly preferred compounds of general formula I are those wherein

X denotes an oxygen atom,

R₁ denotes a hydrogen atom,

R₂ denotes a carboxy group, a straight-chain or branchedC₁₋₄-alkoxycarbonyl group or a phenoxycarbonyl group,

a straight-chain or branched C₁₋₃-alkoxy-carbonyl group, which isterminally substituted in the alkyl moiety by a phenyl, carboxy,C₁₋₃-alkoxycarbonyl, aminocarbonyl, C₁₋₃-alkylaminocarbonyl ordi-(C₁₋₃-alkyl)-aminocarbonyl group,

a straight-chain or branched C₂₋₃-alkoxy-carbonyl group which isterminally substituted in the alkyl moiety by a hydroxy, C₁₋₃-alkoxy,amino, C₁₋₃-alkylamino or di-(C₁₋₃-alkyl)-amino group,

an aminocarbonyl or methylaminocarbonyl group, an ethylaminocarbonylgroup optionally substituted in the 2 position of the ethyl group by ahydroxy or C₁₋₃-alkoxy group or a di-(C₁₋₂-alkyl)-aminocarbonyl group,

R₃ denotes a C₁₋₄-alkyl group or a phenyl group which may be substitutedby a fluorine, chlorine or bromine atom, by a trifluoromethyl,C₁₋₃-alkyl, hydroxy or C₁₋₃-alkoxy group,

R₄ denotes a C₅₋₆-cycloalkyl group,

wherein the methylene group in position 4 of the cyclohexyl group may besubstituted by an amino, C₁₋₃-alkylamino or di-(C₁₋₃-alkyl)-amino groupor replaced by an —NH or —N(C₁₋₃-alkyl) group,

a phenyl group, a phenyl group disubstituted by C₁₋₃-alkyl, C₁₋₃-alkoxyor nitro groups, wherein the substituents may be identical or different,or

a phenyl group substituted by the group R₆, which may additionally besubstituted by a fluorine, chlorine or bromine atom or by an amino ornitro group, wherein R₆ denotes a fluorine, chlorine or bromine atom,

a C₁₋₃-alkyl, C₁₋₃-alkoxy, nitro, amino or C₅₋₆-cycloalkyl group,

a pyrrolyl, pyrazolyl, imidazolyl, triazolyl or tetrazolyl group boundvia a carbon atom, wherein the abovementioned heteroaromatic groups inthe carbon skeleton may be substituted by a C₁₋₃-alkyl group or ahydrogen atom bound to a nitrogen atom may be replaced by a C₁₋₃-alkylor phenyl-C₁₋₃-alkyl group,

the group of formula

a carboxy, C₁₋₄-alkoxycarbonyl, phenyl-C₁₋₃-alkyl-amino-carbonyl orC₅₋₇-cycloalkyl-carbonyl group,

a 5 or 6-membered cycloalkyleneimino group, wherein

the methylene group in position 4 of the piperidino group may bereplaced by an oxygen or sulphur atom, by an —NH or —N(C₁₋₃-alkyl)group,

an unbranched C₁₋₃-alkyl group terminally substituted by the group R₇,wherein

R₇ denotes a C₅₋₇-cycloalkyl group,

wherein in a 5 or 6-membered cycloalkyl group a —(CH₂)₂ group may bereplaced by a —CO—NH group, a —(CH₂)₃ group may be replaced by an—NH—CO—NH— or a —(CH₂)₄ group may be replaced by an —NH—CO—NH—CO group,whilst in each case a hydrogen atom bound to a nitrogen atom may bereplaced by a C₁₋₃-alkyl group,

a phenyl or pyridinyl group or a pyrrolyl, pyrazolyl, imidazolyl ortriazolyl group bound via a carbon or nitrogen atom, wherein theabovementioned heteroaromatic groups in the carbon skeleton may besubstituted by a C₁₋₃-alkyl group or a hydrogen atom bound to a nitrogenatom may be replaced by a C₁₋₃-alkyl group,

a hydroxy or C₁₋₃-alkoxy group,

an amino, C₁₋₆-alkylamino, di-(C₁₋₆-alkyl)-amino, phenylamino,N-phenyl-C₁₋₃-alkylamino, phenyl-C₁₋₃-alkylamino orN—(C₁₋₃-alkyl)-phenyl-C₁₋₃-alkylamino group,

a ω-hydroxy-C₂₋₃-alkyl-amino, N—(C₁₋₃-alkyl)-ω-hydroxy-C₂₋₃-alkylamino,di-(ω-hydroxy-C₂₋₃-alkyl)-amino or di-(ω—(C₁₋₃-alkoxy)-C₂₋₃-alkyl)-aminogroup,

a C₁₋₃-alkylcarbonylamino-C₂₋₃-alkyl-amino orC₁₋₃-alkylcarbonylamino-C₂₋₃-alkyl-N—(C₁₋₃-alkyl)-amino group,

a C₁₋₃-alkylsulphonylamino, N—(C₁₋₃-alkyl)-C₁₋₃-alkylsulphonylamino,C₁₋₃-alkylsulphonylamino- —C₂₋₃-alkylamino or C₁₋₃-alkylsulphonylamino-—C₂₋₃-alkyl-N—(C₁₋₃-alkyl)-amino group,

a hydroxycarbonyl-C₁₋₃-alkylamino orN—(C₁₋₃-alkyl)-hydroxycarbonyl-C₁₋₃-alkyl-amino group,

a guanidino group wherein a hydrogen atom may be replaced by aC₁₋₃-alkyl group,

a group of formula

—N(R₈)—CO—(CH₂)_(n)—R₉  (II),

wherein

R₈ denotes a hydrogen atom or a C₁₋₃-alkyl group,

n denotes one of the numbers 0, 1, 2 or 3 and

R₉ denotes an amino, C₁₋₃-alkylamino, di-(C₁₋₃-alkyl)-amino orC₁₋₄-alkoxy group, a 5- or 6-membered cycloalkyleneimino group, whereinthe methylene group in position 4 of the piperidino group may bereplaced by an —NH, —N(C₁₋₃-alkyl) or —N(C₁₋₃-alkyl-carbonyl) group, or,if n denotes one of the numbers 1, 2 or 3, R₉ may also denote a hydrogenatom,

a group of formula

—N(R₁₀)—(CH₂)_(m)—(CO)_(o)—R₁₁  (III),

wherein

R₁₀ denotes a hydrogen atom or a C₁₋₃-alkyl group,

m denotes one of the numbers 1, 2 or 3,

o denotes the number 1 or, if m is one of the numbers 2 or 3, o may alsodenote the number 0 and

R₁₁ denotes an amino, C₁₋₃-alkylamino, di-(C₁₋₃-alkyl)-amino,C₁₋₄-alkoxy or methoxy-C₁₋₃-alkoxy group or a 5- or 6-memberedcycloalkyleneimino group, wherein the methylene group in position 4 ofthe piperidino group may be replaced by an —NH, —N(C₁₋₃-alkyl) or—N(C₁₋₃-alkyl-carbonyl) group,

an azetidino, pyrrolidino, piperidino, 2,6-dimethyl-piperidino,3,5-dimethyl-piperidino or azepino group, wherein

the methylene group in position 3 of the pyrrolidino group may besubstituted by a hydroxy group,

the methylene group in position 4 of the piperidino group may besubstituted by a hydroxy, hydroxy-C₁₋₃-alkyl or C₁₋₃-alkoxy group or

may be replaced by an oxygen or sulphur atom, by a sulphinyl, sulphonyl,—NH, —N(C₁₋₃-alkyl), —N(C₁₋₃-alkyl-carbonyl), —N(benzoyl) or—N(phenyl-C₁₋₃-alkyl-carbonyl) group,

wherein a methylene group linked to an imino-nitrogen atom of thepyrrolidino, piperidino or piperazino group may be replaced by acarbonyl group,

or R₆ denotes a straight-chain C₁₋₃-alkyl group which is terminallysubstituted by a carboxy or C₁₋₃-alkoxy-carbonyl group,

a group of formula

—N(R₁₂)—CO—(CH₂)_(p)—R₁₃  (IV),

wherein

R₁₂ denotes a hydrogen atom, a C₁₋₃-alkyl or phenyl-C₁₋₃-alkyl group,

p denotes one of the numbers 0, 1 or 2 and

R₁₃ denotes an amino, C₁₋₄-alkylamino, di-(C₁₋₄-alkyl)-amino,benzylamino, N—(C₁₋₃-alkyl)-benzylamino, C₁₋₃-alkoxy-C₁₋₃-alkylamino,N—(C₁₋₃-alkyl)-C₁₋₃-alkoxy-C₁₋₃-alkylamino, di-(2-methoxy-ethyl)-amino,di-(ω-hydroxy-C₂₋₃-alkyl)-amino or aminocarbonyl-methyl-N-(methyl)-aminogroup,

a pyrrolyl, pyrazolyl or imidazolyl group bound via a nitrogen atom andoptionally substituted by a C₁₋₃-alkyl group,

a pyrrolidino, piperidino, morpholino, thiomorpholino or a piperazinogroup optionally substituted in the 4 position by a C₁₋₃-alkyl,phenyl-C₁₋₃-alkyl, C₁₋₃-alkylcarbonyl or C₁₋₄-alkoxycarbonyl group or,if n denotes the number 1 or 2, it may also denote a hydrogen atom,

a group of formula

—N(R₁₄)—(CH₂)_(q)—(CO)_(r)—R₁₅  (V),

wherein

R₁₄ denotes a hydrogen atom, a C₁₋₄-alkyl, C₁₋₃-alkyl-carbonyl,phenylcarbonyl, phenyl-C₁₋₃-alkylcarbonyl, furyl-carbonyl,pyridinyl-carbonyl, furyl-C₁₋₃-alkylcarbonyl,pyridinyl-C₁₋₃-alkylcarbonyl, C₁₋₄-alkylsulphonyl, phenylsulphonyl orphenyl-C₁₋₃-alkylsulphonyl group,

q denotes one of the numbers 1, 2 or 3,

r denotes the number 1 or, if q is one of the numbers 2 or 3, it mayalso denote the number 0 and

R₁₅ denotes an amino, C₁₋₄-alkylamino, di-(C₁₋₄-alkyl)-amino,phenylamino, N—(C₁₋₄-alkyl)-phenylamino, benzylamino orN—(C₁₋₄-alkyl)-benzylamino group,

or a group of formula

—N(R₁₆)—SO₂—R₁₇  (VI),

wherein

R₁₆ denotes a hydrogen atom or a C₁₋₃-alkyl group optionally terminallysubstituted by a cyano, trifluoromethyl-carbonylamino orN—(C₁₋₃-alkyl)-trifluoromethyl-carbonyl-amino group and

R₁₇ denotes a C₁₋₃-alkyl group,

wherein all the single-bonded or fused phenyl groups contained in thegroups mentioned under R₆ may be substituted by a fluorine, chlorine orbromine atom, by a methyl, trifluoromethyl, methoxy, nitro or cyanogroup and

R₅ denotes a hydrogen atom,

wherein a hydrogen atom bound to a nitrogen atom in the abovementionedgroups may be replaced by an acetyl or tert.butoxycarbonyl group,

the carboxy groups contained in the abovementioned groups may also bepresent in the form of the tert.butoxycarbonyl precursor group and

the saturated alkyl and alkoxy moieties contained in the abovementionedgroups, which contain more than 2 carbon atoms, may be straight-chain orbranched, unless otherwise stated,

the tautomers, the diastereomers, the enantiomers, the mixtures thereofand the salts thereof.

One subgroup of particularly preferred compounds of general formula Ideserving special mention comprises those wherein

X, R₁, R₃ and R₅ are as hereinbefore defined,

R₂ denotes a straight-chain or branched C₁₋₄-alkoxycarbonyl group or aphenoxycarbonyl group,

a straight-chain or branched C₁₋₃-alkoxycarbonyl group, which isterminally substituted in the alkyl moiety by a phenyl- carboxy,C₁₋₃-alkoxycarbonyl, aminocarbonyl, C₁₋₃-alkylaminocarbonyl ordi-(C₁₋₃-alkyl)-aminocarbonyl group, or

a straight-chain or branched C₂₋₃-alkoxy-carbonyl group, which isterminally substituted in the alkyl moiety by a hydroxy, C₁₋₃-alkoxy,amino, C₁₋₃-alkylamino or di-(C₁₋₃-alkyl)-amino group, and

R₄ denotes an R₇-(n-C₁₋₃-alkyl)-phenyl group, wherein

R₇ denotes an amino, C₁₋₆-alkylamino, di-(C₁₋₄-alkyl)-amino,ω-hydroxy-C₂₋₃-alkyl-amino, N—(C₁₋₃-alkyl)-ω-hydroxy-C₂₋₃-alkyl-amino,di-(ω-hydroxy-C₂₋₃-alkyl)-amino or di-(ω—(C₁₋₃-alkoxy)-C₂₋₃-alkyl)-aminogroup,

or a phenyl group substituted by the group of formula

—N(R₁₂)—CO—(CH₂)_(p)—R₁₃  (IV),

wherein R₁₂, p and R₁₃ are as hereinbefore defined,

the tautomers, the diastereomers, the enantiomers, the mixtures thereofand the salts thereof.

A second subgroup of particularly preferred compounds of general formulaI deserving special mention comprises those wherein

X, R₁, R₃ and R₅ are as hereinbefore defined,

R₂ denotes an aminocarbonyl or methylaminocarbonyl group, anethylaminocarbonyl group optionally substituted in the 2 position of theethyl group by a hydroxy or C₁₋₃-alkoxy group or adi-(C₁₋₂-alkyl)-aminocarbonyl group and

R₄ denotes a R₇-(n-C₁₋₃-alkyl)-phenyl group, wherein

R₇ denotes an amino, C₁₋₆-alkylamino, di-(C₁₋₄-alkyl)-amino,ω-hydroxy-C₂₋₃-alkyl-amino, N—(C₁₋₃-alkyl)-ω-hydroxy- -C₂₋₃-alkyl-amino,di-(ω-hydroxy-C₂₋₃-alkyl)-amino or di-(ω—(C₁₋₃-alkoxy)-C₂₋₃-alkyl)-aminogroup,

or a phenyl group substituted by the group of formula

—N(R₁₂)—CO—(CH₂)_(p)—R₁₃  (IV),

wherein R₁₂, p and R₁₃ are as hereinbefore defined,

the tautomers, the diastereomers, the enantiomers, the mixtures thereofand the salts thereof.

Most particularly preferred compounds of general formula I are thosewherein

X denotes an oxygen atom,

R₁ and R₅ each denote a hydrogen atom,

R₂ denotes a methoxycarbonyl, ethoxycarbonyl or aminocarbonyl group,

R₃ denotes a phenyl group and

R₄ denotes a phenyl group monosubstituted by the group R₆, wherein

R₆ denotes an N-methyl-imidazol-2-yl group,

an unbranched C₁₋₃-alkyl group which is terminally substituted by aC₁₋₄-alkylamino, di-(C₁₋₄-alkyl)-amino, piperidino or2,6-dimethyl-piperidino group,

a group of formula

—N(R₁₂)—CO—(CH₂)_(p)—R₁₃  (IV),

wherein R₁₂ denotes a C₁₋₃-alkyl group,

p denotes one of the numbers 1 or 2 and

R₁₃ denotes a di-(C₁₋₃-alkyl)-amino group,

or a group of formula

—N(R₁₄)—(CH₂)_(q)—(CO)_(r)—R₁₅  (V),

wherein

R₁₄ denotes a C₁₋₃-alkyl-carbonyl or C₁₋₃-alkylsulphonyl group,

q denotes one of the numbers 1, 2 or 3,

r denotes the number 1 or, if q is one of the numbers 2 or 3, r may alsodenote the number 0 and

R₁₅ denotes a di-(C₁₋₃-alkyl)-amino group,

wherein the saturated alkyl moieties contained in the abovementionedgroups which contain more than 2 carbon atoms may be straight-chain orbranched, unless otherwise stated,

the tautomers, the diastereomers, the enantiomers, the mixtures thereofand the salts thereof.

A subgroup of most particularly preferred compounds of general formula Ideserving special mention comprises those wherein

X, R₁, R₃ and R₅ are as hereinbefore defined,

R₂ denotes a methoxycarbonyl or ethoxycarbonyl group and

R₄ denotes a di-(C₁₋₃-alkyl)-amino-C₁₋₃-alkylphenyl group or a phenylgroup substituted by the group of formula

—N(R₁₂)—CO—(CH₂)_(p)—R₁₃  (IV),

wherein R₁₂, p and R₁₃ are as hereinbefore defined,

the tautomers, the diastereomers, the enantiomers, the mixtures thereofand the salts thereof.

The following are mentioned as examples of particularly preferredcompounds:

-   (a)    3-Z-[1-(4-(piperidin-1-yl-methyl)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone,-   (b)    3-Z-[(1-(4-(piperidin-1-yl-methyl)-anilino)-1-phenyl-methylene]-6-carbamoyl-2-indolinone,-   (c)    3-Z-[1-(4-(piperidin-1-yl-methyl)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone,-   (d)    3-Z-[1-(4-(dimethylaminomethyl)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone,-   (e)    3-Z-[1-(4-((2,6-dimethyl-piperidin-1-yl)-methyl)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone,-   (f)    3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-acetyl-amino)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone,-   (g)    3-Z-[1-(4-(N-(3-dimethylamino-propyl)-N-acetyl-amino)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone,-   (h)    3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-methylsulphonyl-amino)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone,-   (i)    3-Z-[1-(4-(dimethylaminomethyl)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone,-   (j)    3-Z-[1-(4-(N-acetyl-N-dimethylaminocarbonylmethyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone,-   (k)    3-Z-[1-(4-ethylaminomethyl-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone,-   (l)    3-Z-[1-(4-(1-methyl-imidazol-2-yl)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone,-   (m)    3-Z-[1-(4-(N-dimethylaminomethylcarbonyl-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone,-   (n) 3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-methylsulphonyl    amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone,-   (o)    3-Z-[1-(4-(N-(3-dimethylamino-propyl)-N-methylsulphonyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone,-   (p)    3-Z-[1-(4-(N-dimethylaminocarbonylmethyl-N-methylsulphonyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone,-   (q)    3-Z-[1-(4-(N-((2-dimethylamino-ethyl)-carbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone,-   (r)    3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-acetyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinon    and-   (s)    3-Z-[1-(4-methylaminomethyl-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone,

their tautomers, their stereoisomers or the physiologically acceptablesalts thereof.

Another subgroup of compounds of general formula I comprises thosewherein

X denotes an oxygen or sulphur atom,

R₁ denotes a hydrogen atom or a prodrug group such as aC₁₋₄-alkoxycarbonyl or C₂₋₄-alkanoyl group,

R₂ denotes a carboxy group, a straight-chain or branchedC₁₋₆-alkoxycarbonyl group, a C₅₋₇-cycloalkoxycarbonyl orphenyl-C₁₋₃-alkoxycarbonyl group, an aminocarbonyl orC₁₋₂-alkylaminocarbonyl group or, if R₄ does not denote anaminosulphonyl-phenyl or N—(C₁₋₅-alkyl)-C₁₋₃-alkylaminocarbonyl-phenylgroup, a di-(C₁₋₂-alkyl)-aminocarbonyl group,

R₃ denotes a hydrogen atom, a C₁₋₆-alkyl, C₃₋₇-cycloalkyl,trifluoromethyl or heteroaryl group,

a phenyl or naphthyl group, a phenyl or naphthyl group mono- ordisubstituted by a fluorine, chlorine, bromine or iodine atom, by atrifluoromethyl, C₁₋₃-alkyl or C₁₋₃-alkoxy group, whilst in the event ofdisubstitution the substituents may be identical or different andwherein the abovementioned unsubstituted as well as the mono- anddisubstituted phenyl and naphthyl groups may additionally be substitutedby a hydroxy, hydroxy-C₁₋₃-alkyl or C₁₋₃-alkoxy-C₁₋₃-alkyl group,

by a cyano, carboxy, carboxy-C₁₋₃-alkyl, C₁₋₃-alkoxycarbonyl,aminocarbonyl, C₁₋₃-alkylamino-carbonyl or di-(C₁₋₃-alkyl)-aminocarbonylgroup,

by a nitro group,

by an amino, C₁₋₃-alkylamino, di-(C₁₋₃-alkyl)-amino or amino-C₁₋₃-alkylgroup,

by a C₁₋₃-alkylcarbonylamino, N—(C₁₋₃-alkyl)-C₁₋₃-alkylcarbonylamino,C₁₋₃-alkylcarbonylamino-C₁₋₃-alkyl,N—(C₁₋₃-alkyl)-C₁₋₃-alkylcarbonylamino-C₁₋₃-alkyl,C₁₋₃-alkylsulphonylamino, C₁₋₃-alkylsulphonylamino-C₁₋₃-alkyl,N—(C₁₋₃-alkyl)-C₁₋₃-alkylsulphonylamino-C₁₋₃-alkyl oraryl-C₁₋₃-alkylsulphonylamino group,

by a cycloalkylamino, cycloalkyleneimino, cycloalkyleneiminocarbonyl,cycloalkyleneimino-C₁₋₃-alkyl, cycloalkyleneiminocarbonyl-C₁₋₃-alkyl orcycloalkyleneiminosulphonyl-C₁₋₃-alkyl group having 4 to 7 ring membersin each case, whilst in each case the methylene group in position 4 of a6- or 7-membered cycloalkyleneimino group may be replaced by an oxygenor sulphur atom, by a sulphinyl, sulphonyl, —NH or —N(C₁₋₃-alkyl) group,

or by a heteroaryl or heteroaryl-C₁₋₃-alkyl group,

R₄ denotes a C₃₋₇-cycloalkyl group,

whilst the methylene group in the 4 position of a 6- or 7-memberedcycloalkyl group may be substituted by an amino, C₁₋₃-alkylamino ordi-(C₁₋₃-alkyl)-amino group or replaced by an —NH or —N(C₁₋₃-alkyl)group,

or a phenyl group substituted by the group R₆, which may additionally besubstituted by a fluorine, chlorine, bromine or iodine atom, by aC₁₋₅-alkyl, trifluoromethyl, C₁₋₃-alkoxy, carboxy, C₁₋₃-alkoxycarbonyl,aminosulphonyl, nitro or cyano group, wherein

R₆ denotes a hydrogen, fluorine, chlorine, bromine or iodine atom,

a cyano, nitro, C₁₋₅-alkyl, C₃₋₇-cycloalkyl, trifluoromethyl, phenyl,tetrazolyl or heteroaryl group,

a C₁₋₃-alkoxy group optionally substituted by 1 to 3 fluorine atoms, aC₁₋₃-alkoxy-C₁₋₃-alkoxy, phenyl-C₁₋₃-alkoxy, amino-C₂₋₃-alkoxy,C₁₋₃-alkylamino-C₂₋₃-alkoxy, di-(C₁₋₃-alkyl)-amino-C₂₋₃-alkoxy,phenyl-C₁₋₃-alkylamino-C₂₋₃-alkoxy,N—(C₁₋₃-alkyl)-phenyl-C₁₋₃-alkylamino-C₂₋₃-alkoxy,C₅₋₇-cycloalkyleneimino-C₂₋₃-alkoxy or C₁₋₃-alkylmercapto group,

a carboxy, C₁₋₄-alkoxycarbonyl, aminocarbonyl,C₁₋₃-alkyl-amino-carbonyl, N—(C₁₋₅-alkyl)-C₁₋₃-alkylaminocarbonyl,phenyl-C₁₋₃-alkylamino-carbonyl,N—(C₁₋₃-alkyl)-phenyl-C₁₋₃-alkylamino-carbonyl, piperazinocarbonyl orN—(C₁₋₃-alkyl)-piperazinocarbonyl group,

a C₁₋₃-alkylaminocarbonyl or N—(C₁₋₅-alkyl)-C₁₋₃-alkylaminocarbonylgroup wherein an alkyl moiety is substituted by a carboxy orC₁₋₃-alkoxycarbonyl group or is substituted in the 2 or 3 position by adi-(C₁₋₃-alkyl)-amino, piperazino, N—(C₁₋₃-alkyl)-piperazino or a 4- to7-membered cycloalkyleneimino group,

a 4- to 7-membered cycloalkyleneimino group, wherein

a methylene group linked to the imino group may be replaced by acarbonyl or sulphonyl group or the cycloalkylene moiety may be fused toa phenyl ring or

one or two hydrogen atoms may each be replaced by a C₁₋₃-alkyl groupand/or

in each case the methylene group in the 4 position of a 6- or 7-memberedcycloalkyleneimino group may be substituted by a carboxy,C₁₋₃-alkoxycarbonyl, aminocarbonyl, C₁₋₃-alkylaminocarbonyl,di-(C₁₋₃-alkyl)-aminocarbonyl, phenyl-C₁₋₃-alkylamino orN—(C₁₋₃-alkyl)-phenyl-C₁₋₃-alkylamino group or

may be replaced by an oxygen or sulphur atom, by a sulphinyl,

sulphonyl, —NH, —N(C₁₋₃-alkyl), —N(phenyl), —N(C₁₋₃-alkyl-carbonyl) or—N(benzoyl) group,

a C₁₋₄-alkyl group which may be substituted

by a hydroxy or C₁₋₃-alkoxy group,

by an amino, C₁₋₇-alkylamino, di-(C₁₋₇-alkyl)-amino,di-N—(C₁₋₃-alkyl)-amino-C₂₋₃-alkylamino,tri-N,N,N′—(C₁₋₃-alkyl)-amino-C₂₋₃-alkylamino, phenylamino,N-phenyl-C₁₋₃-alkyl-amino, phenyl-C₁₋₃-alkylamino,N—(C₁₋₃-alkyl)-phenyl-C₁₋₃-alkylamino or di-(phenyl-C₁₋₃-alkyl)-aminogroup,

by a C₁₋₃-alkylcarbonylamino, N—(C₁₋₃-alkyl)-C₁₋₃-alkylcarbonylamino,C₁₋₃-alkoxycarbonyl-C₁₋₃-alkylamino orN—(C₁₋₃-alkyl)-C₁₋₃-alkoxycarbonyl-C₁₋₃-alkylamino group,

by a C₄₋₇-cycloalkylamino, C₄₋₇-cycloalkyl-C₁₋₃-alkylamino orC₄₋₇-cycloalkenylamino group wherein position 1 of the ring is notinvolved in the double bond and wherein the abovementioned groups mayeach additionally be substituted at the amino-nitrogen atom by aC₁₋₃-alkyl group wherein some or all of the hydrogen atoms are replacedby fluorine atoms, by a C₅₋₇-cycloalkyl, C₂₋₄-alkenyl or C₁₋₄-alkylgroup,

by a 4- to 7-membered cycloalkyleneimino group, wherein

a methylene group linked to the imino group may be replaced by acarbonyl or sulphonyl group or

the cycloalkylene moiety may be fused to a phenyl group or to anoxazolo, imidazolo, thiazolo, pyridino, pyrazino or

pyrimidino group optionally substituted by a fluorine, chlorine, bromineor iodine atom, by a nitro, C₁₋₃-alkyl, C₁₋₃-alkoxy or amino group or

one or two hydrogen atoms may each be replaced by a C₁₋₃-alkyl,C₅₋₇-cycloalkyl or phenyl group and/or

in each case the methylene group in the 4 position of a 6- or 7-memberedcycloalkyleneimino group may be substituted by a hydroxy, carboxy,C₁₋₄-alkoxycarbonyl, aminocarbonyl, C₁₋₃-alkylaminocarbonyl,di-(C₁₋₃-alkyl)-aminocarbonyl, phenyl-C₁₋₃-alkylamino orN—(C₁₋₃-alkyl)-phenyl-C₁₋₃-alkylamino group or

may be replaced by an oxygen or sulphur atom, by a sulphinyl,

sulphonyl, —NH, —N(C₁₋₃-alkyl), —N(phenyl), —N(C₁₋₃-alkyl-carbonyl) or—N(benzoyl) group,

by a carboxy, C₁₋₃-alkoxycarbonyl, aminocarbonyl,C₁₋₃-alkylaminocarbonyl or di-(C₁₋₃-alkyl)-aminocarbonyl group or

by a 4- to 7-membered cycloalkyleneiminocarbonyl group,

an amino, pyrrolidino, piperidino, morpholino, benzoylamino orN—(C₁₋₃-alkyl)-benzoylamino group,

an N—(C₁₋₃-alkyl)-C₂₋₄-alkanoylamino group which is additionallysubstituted in the alkyl moiety by a carboxy or C₁₋₃-alkoxycarbonylgroup,

a group of formula

—N(R₈)—CO—(CH₂)_(n)—R₉  (II),

wherein

R₈ denotes a hydrogen atom or a C₁₋₃-alkyl group,

n denotes one of the numbers 0, 1, 2 or 3 and

R₉ denotes an amino, C₁₋₄-alkylamino, phenylamino,N—(C₁₋₄-alkyl)-phenylamino, benzylamino, N—(C₁₋₄-alkyl)-benzylamino ordi-(C₁₋₄-alkyl)-amino group, a 4- to 7-membered cycloalkyleneiminogroup, whilst in each case the methylene group in the 4 position of a 6-or 7-membered cycloalkyleneimino group may be replaced by an oxygen orsulphur atom, by a sulphinyl,

sulphonyl, —NH, —N(C₁₋₃-alkyl), —N(phenyl), —N(C₁₋₃-alkyl-carbonyl) or—N(benzoyl) group, or, if n denotes one of the numbers 1, 2 or 3, it mayalso denote a hydrogen atom,

a group of formula

—N(R₁₀)—(CH₂)_(m)—(CO)_(o)—R₁₁  (III),

wherein

R₁₀ denotes a hydrogen atom, a C₁₋₃-alkyl group, a C₁₋₃-alkylcarbonyl,arylcarbonyl, phenyl-C₁₋₃-alkylcarbonyl, C₁₋₃-alkylsulphonyl,arylsulphonyl or phenyl-C₁₋₃-alkylsulphonyl group,

m denotes one of the numbers 1, 2, 3 or 4,

o denotes one of the numbers 0 or 1 and

R₁₁ denotes an amino, C₁₋₄-alkylamino, phenylamino,N—(C₁₋₄-alkyl)-phenylamino, benzylamino, N—(C₁₋₄-alkyl)-benzylamino ordi-(C₁₋₄-alkyl)-amino group, a 4- to 7-membered cycloalkyleneiminogroup, wherein the cycloalkylene moiety may be fused to a phenyl ring orin each case the methylene group in the 4 position of a 6- or 7-memberedcycloalkyleneimino group may be replaced by an oxygen or sulphur atom,by a sulphinyl, sulphonyl, —NH, —N(C₁₋₃-alkyl), —N(phenyl),—N(C₁₋₃-alkyl-carbonyl) or —N(benzoyl) group, a C₁₋₃-alkoxy group or adi-(C₁₋₄-alkyl)-amino-C₁₋₃-alkylamino group optionally substituted inthe 1 position by a C₁₋₃-alkyl group,

or an N—(C₁₋₃-alkyl)-C₁₋₅-alkylsulphonylamino orN—(C₁₋₃-alkyl)-phenylsulphonylamino group wherein the alkyl moiety isadditionally substituted by a cyano or carboxy group,

wherein all the single-bonded or fused phenyl groups contained in thegroups mentioned under R₆ may be mono- or disubstituted by fluorine,chlorine, bromine or iodine atoms, by C₁₋₅-alkyl, trifluoromethyl,C₁₋₃-alkoxy, carboxy, C₁₋₃-alkoxycarbonyl, aminosulphonyl, nitro orcyano groups, wherein the substituents may be identical or different, ortwo adjacent hydrogen atoms of the phenyl groups may be replaced by amethylenedioxy group,

and

R₅ denotes a hydrogen atom or a C₁₋₃-alkyl group,

wherein by an aryl group is meant a phenyl or naphthyl group optionallymono- or disubstituted by a fluorine, chlorine, bromine or iodine atom,by a trifluoromethyl, C₁₋₃-alkyl or C₁₋₃-alkoxy group and

by a heteroaryl group is meant a monocyclic 5- or 6-membered heteroarylgroup optionally substituted by a C₁₋₃-alkyl group, wherein the6-membered heteroaryl group contains one, two or three nitrogen atomsand the 5-membered heteroaryl group contains an imino group optionallysubstituted by a C₁₋₃-alkyl group, an oxygen or sulphur atom or an iminogroup optionally substituted by a C₁₋₃-alkyl group and an oxygen orsulphur atom or one or two nitrogen atoms, and moreover a phenyl ringmay be fused to the abovementioned monocyclic heterocyclic groups viatwo adjacent carbon atoms, the saturated alkyl and alkoxy moietiespresent in the groups defined above which contain more than 2 carbonatoms also include the branched isomers thereof such as, for example,the isopropyl, tert.butyl or isobutyl group, unless otherwise stated,and

additionally any carboxy, amino or imino group present may besubstituted by a group which can be cleaved in vivo, the isomers and thesalts thereof.

A further subgroup of compounds of general formula I which deservesspecial mention is the subgroup wherein the substituent in the 6position of the substituted indolinone of general formula I comprises asubstituted amido group.

The above exemplified compounds, their tautomers, their stereoisomers orthe physiologically acceptable salts thereof, as well as theirmanufacturing process, have been described in WO 01/27081, the contentof which is incorporated herein by reference.

Further compounds in accordance with the above general formula I whichare preferred within the meaning of the present invention are thefollowing compounds:

-   (t)    3-Z-[1-(4-(2-dimethylamino-ethoxy)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (u)    3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone,-   (v)    3-Z-[1-(3-cyano-4-(N-dimethylaminomethylcarbonyl-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (w) 3-Z-[1-(3-methoxy-4-(N-dimethylaminomethylcarbonyl-N    methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (x)    3-Z-[1-(4-(N-aminomethylcarbonyl-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (y)    3-Z-[1-(4-(N—(N-(2-dimethylamino-ethyl)-N-methyl-aminomethylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (z)    3-Z-[1-(4-(N-(di-(2-hydroxy-ethyl)-amino-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (aa)    3-Z-[1-(4-(N-(imidazol-1-yl-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (ab)    3-Z-[1-(4-(N-dimethylaminomethylcarbonyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (ac)    3-Z-[1-(4-(N-((4-methyl-[1,4]diazepan-1-yl)-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (ad)    3-Z-[1-(4-(N-((1-methyl-piperidin-4-yl)-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (ae)    3-Z-[1-(2,3-dimethyl-4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (af)    3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (ag)    3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-carbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (ah)    3-Z-[1-(4-(N-(3-dimethylamino-propyl)-N-acetyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (ai)    3-Z-[1-(4-(N-((3-dimethylamino-propyl)-aminocarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (aj)    3-Z-[1-anilino-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (ak)    3-Z-[1-(4-(N-methyl-N-methylsulphonyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (al)    3-Z-[1-cyclohexylamino-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (am)    3-Z-[1-(4-(4-methylpiperazin-1-yl-methyl)-anilino)-1-phenyl-methylene]-6-carboxy-2-indolinone-   (an)    3-Z-[1-(4-methylaminomethyl-anilino)-1-phenyl-methylene]-6-carboxy-2-indolinone-   (ao)    3-Z-[1-(4-(morpholin-4-yl-methyl)-anilino)-1-phenyl-methylene]-6-carboxy-2-indolinone-   (ap)    3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-methylsulphonyl-amino)-anilino)-1-phenyl-methylene]-6-carboxy-2-indolinone-   (aq)    3-Z-[1-(4-(di-(2-hydroxy-ethyl)-amino-methyl)-anilino)-1-phenyl-methylene]-6-carboxy-2-indolinone-   (ar)    3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-carboxy-2-indolinone-   (as) 3-Z-[1-(4-(N-(morpholin-4-yl-methylcarbonyl)-N-me    amino)-anilino)-1-phenyl-methylene]-6-carboxy-2-indolinone-   (at)    3-Z-[1-(4-(N—(N-(2-dimethylamino-ethyl)-N-methyl-aminomethylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-carboxy-2-indolinone-   (au)    3-Z-[1-(4-(2-dimethylamino-ethoxy)-anilino)-1-phenyl-methylene]-6-carboxy-2-indolinone-   (av) 3-Z-[1-cyclohexylamino-1-phenyl-methylene]-6-carb indolinone-   (aw) 3-Z-[1-(4-dimethylaminomethyl-anilino)-1-(3-(2-ca    ethyl)-phenyl)-methylene]-6-methoxycarbonyl-2-indolino-   (ax)    3-Z-[1-(4-(2-dimethylamino-ethyl)-anilino)-1-(3-(carboxy-ethyl)-phenyl)-methylene]-6-methoxycarbonyl-2-indolinone-   (ay)    3-Z-[1-(4-(1-methyl-imidazol-2-yl)-anilino)-1-(3-carboxy-ethyl)-phenyl)-methylene]-6-methoxycarbonyl-2-indolinone-   (az) 3-Z-[1-(4-dimethylaminomethyl-anilino)-1-(4-(2-ca    ethyl)-phenyl)-methylene]-6-methoxycarbonyl-2-indolinone-   (ba)    3-Z-[1-(4-(2-dimethylamino-ethyl)-anilino)-1-phenyl-methylene]-6-ethylmethylcarbamoyl-2-indolinone-   (bb)    3-Z-[1-(4-dimethylaminomethyl-anilino)-1-phenyl-methylene]-6-ethylmethylcarbamoyl-2-indolinone-   (bc)    3-Z-[1-((1-methyl-piperidin-4-yl)-amino-1-phenyl-methylene]-6-ethylmethylcarbamoyl-2-indolinone-   (bd)    3-Z-[1-(trans-4-dimethylamino-cyclohexylamino)-1-phenyl-methylene]-6-ethylmethylcarbamoyl-2-indolinone-   (be)    3-Z-[1-(4-(2-diethylamino-ethoxy)-anilino)-1-phenyl-methylene]-6-ethylmethylcarbamoyl-2-indolinone-   (bf)    3-Z-[1-(4-(N-(3-dimethylamino-propyl)-N-propionyl-amino)-anilino)-1-phenyl-methylene]-6-ethylmethylcarbamoyl-2-indolinone-   (bg)    3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-ethylmethylcarbamoyl-2-indolinone-   (bh)    3-Z-[1-cyclohexylamino-1-phenyl-methylene]-6-ethylmethylcarbamoyl-2-indolinone-   (bi)    3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-acetyl-amino)-anilino)-1-phenyl-methylene]-6-ethylmethylcarbamoyl-2-indolinone-   (bj)    3-Z-[1-(3-diethylaminomethyl-anilino)-1-phenyl-methylene]-6-ethylmethylcarbamoyl-2-indolinone-   (bk)    3-Z-[1-(4-(N-dimethylaminomethylcarbonyl-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-ethylmethylcarbamoyl-2-indolinone-   (bl)    3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-methylsulponyl-amino)-anilino)-1-phenyl-methylene]-6-ethylmethylcarbamoyl-2-indolinone-   (bm)    3-Z-[1-anilino-1-phenyl-methylene]-6-ethylmethylcarbamoyl-2-indolinone-   (bn)    3-Z-[1-(4-ethylaminomethyl-anilino)-1-phenyl-methylene]-6-ethylmethylcarbamoyl-2-indolinone-   (bo)    3-Z-[1-(4-((2-diethylamino-ethyl)-anilino)-1-phenyl-methylene]-6-ethylmethylcarbamoyl-2-indolinone-   (bp)    3-Z-[1-(4-(N-(3-dimethylamino-propyl)-N-acetyl-amino)-anilino)-1-phenyl-methylene]-6-ethylmethylcarbamoyl-2-indolinone-   (bq)    3-Z-[1-(4-(N-methyl-N-methylsulphonyl-amino)-anilino)-1-phenyl-methylene]-6-ethylmethylcarbamoyl-2-indolinon-   (br)    3-Z-[1-(4-methoxycarbonyl-anilino)-1-phenyl-methylene]-6-ethylmethylcarbamoyl-2-indolinone-   (bs)    3-Z-[1-(4-carboxy-anilino)-1-phenyl-methylene]-6-ethylmethylcarbamoyl-2-indolinone-   (bt)    3-Z-[1-(4-(N-(dimethylamino-carbonylmethyl)-N-methylsulphonyl-amino)-anilino)-1-phenyl-methylene]-6-ethylmethylcarbamoyl-2-indolinone-   (bu)    3-Z-[1-(4-(2-dimethylamino-ethoxy)-anilino)-1-phenyl-methylene]-6-ethylcarbamoyl-2-indolinone-   (bv)    3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-ethylcarbamoyl-2-indolinone-   (bw)    3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-methylsulphonyl-amino)-anilino)-1-phenyl-methylene]-6-ethylcarbamoyl-2-indolinone-   (bx)    3-Z-[1-(4-(2-dimethylamino-ethoxy)-anilino)-1-phenyl-methylene]-6-ethylmethylcarbamoyl-2-indolinone-   (by)    3-Z-[1-(4-(N-dimethylaminomethylcarbonyl-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-ethylcarbamoyl-indolinone-   (bz)    3-Z-[1-(4-dimethylaminomethyl-anilino)-1-phenyl-methylene]-6-ethylcarbamoyl-2-indolinone-   (ca)    3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-acetyl-amino)-anilino)-1-phenyl-methylene]-6-ethylcarbamoyl-2-indolinone-   (cb)    3-Z-[1-(4-(N-(3-dimethylamino-propyl)-N-acetyl-amino)-anilino)-1-phenyl-methylene]-6-ethylcarbamoyl-2-indolinone-   (cc)    3-Z-[1-(4-carbamoyl-anilino)-1-phenyl-methylene]-6-ethylmethylcarbamoyl-2-indolinone-   (cd)    3-Z-[1-(4-(N-(2-diethylamino-ethyl)-carbamoyl)-anilino)-1-phenyl-methylene]-6-ethylmethylcarbamoyl-2-indolinone-   (ce)    3-Z-[1-(4-((4-methyl-piperazin-1-yl)-carbonyl)-anilino)-1-phenyl-methylene]-6-ethylmethylcarbamoyl-2-indolinone-   (cf)    3-Z-[1-(4-((4-methyl-piperazin-1-yl)-carbonyl)-anilino)-1-phenyl-methylene]-6-ethylcarbamoyl-2-indolinone-   (cg)    3-Z-[1-(4-((4-ethyl-piperazin-1-yl)-carbonyl)-anilino)-1-phenyl-methylene]-6-ethylmethylcarbamoyl-2-indolino-   (ch)    3-Z-[1-(4-(N-ethyl-N-(2-dimethylamino-ethyl)-carbamoyl)-anilino)-1-phenyl-methylene]-6-ethylmethylcarbamoyl-2-indolinone-   (ci)    3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-diethylcarbamoyl-2-indolinone-   (cj)    3-Z-[1-(4-((cis-3,5-dimethyl-piperazin-1-yl)-carbonyl)-anilino)-1-phenyl-methylene]-6-ethylmethylcarbamoyl-2-indolinone-   (ck)    3-Z-[1-(4-((4-ethyl-piperazin-1-yl)-carbonyl)-anilino)-1-phenyl-methylene]-6-ethylcarbamoyl-2-indolinone-   (cl)    3-Z-[1-(4-(N-(2-diethylamino-ethyl)-carbamoyl)-anilino)-1-phenyl-methylene]-6-ethylmethylcarbamoyl-2-indolinone-   (cm)    3-Z-[1-(4-((cis-3,5-dimethyl-piperazin-1-yl)-carbonyl)-anilino)-1-phenyl-methylene]-6-ethylcarbamoyl-2-indolinone-   (cn)    3-Z-[1-(4-(N-(3-dimethylamino-propyl)-N-methylsulphonyl-amino)-anilino)-1-phenyl-methylene]-6-ethylcarbamoyl-2-indolinone-   (co)    3-Z-[1-(4-(N-dimethylaminomethylcarbonyl-N-methyl-amino)-anilino)-methylene]-6-methoxycarbonyl-2-indolinone-   (cp)    3-Z-[1-(4-dimethylaminomethyl-anilino)-methylene]-6-methoxycarbonyl-2-indolinone-   (cq)    3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-anilino)-methylene]-6-methoxycarbonyl-2-indolinone-   (cr)    3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-anilino)-methylene]-6-ethylcarbamoyl-2-indolinone-   (cs)    3-Z-[1-(4-dimethylaminomethyl-anilino)-methylene]-6-ethylcarbamoyl-2-indolinone-   (ct)    3-Z-[1-(4-(piperidin-1-yl-methyl)-anilino)-methylene]-6-ethylcarbamoyl-2-indolinone-   (cu)    3-Z-[1-(4-(N-(3-dimethylamino-propyl)-N-acetyl-amino)-anilino)-methylene]-6-ethylcarbamoyl-2-indolinone,

their tautomers, their stereoisomers or the physiologically acceptablesalts thereof.

These compounds may be prepared analogously to the compounds of WO01/27081 and using the methods described hereafter.

Abbreviations used:

HOBt=1-hydroxy-1H-benzotriazole

TBTU=O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium-tetrafluoroborate

DEPC=diethyl pyrocarbonate

n.d.=not determined

Examples (t) to (al)

The following compounds of general formula II are prepared analogouslyto the compounds described in WO 01/27081:

Melting Mass point Example A B R⁶ Formula spectrum [° C.] R_(f)-value*(t) —H —H —O(CH₂)₂—NMe₂ C₂₇H₂₇N₃O₄ 456 n.b. 0.30 [m − H]⁻ (A) (u) —H —H

C₃₁H₃₃N₅O₄ 540 [m + H]⁺ 250- 252 0.60 (B) (v) —CN —H—N(Me)—(CO)—CH₂—NMe₂ C₂₉H₂₇N₅O₄ 510 163- 0.35 [m + H]⁺ 165 (A) (w) —OMe—H —N(Me)—(CO)—CH₂—NMe₂ C₂₀H₃₀N₄O₅ 515 160- 0.40 [m + H]⁺ 163 (A) (x) —H—H —N(Me)—(CO)—CH₂—NMe₂ C₂₆H₂₄N₄O₄ 457 221 0.45 [m + H]⁺ (C) (y) —H —H

C₂₄H₂₁N₃O₃ 542 [m + H]⁺ 265 n.d. (z) —H —H

C₃₀H₃₂N₄O₆ 545 [m + H]⁺ 199- 202 0.40 (A) (aa) —H —H

C₂₉H₂₅N₅O₄ 508 [m + H]⁺ 271 0.45 (A) (ab) —H —H —NH—(CO)—CH₂—NMe₂C₂₇H₂₆N₄O₄ 471 250- 0.50 [m + H]⁺ 255 (A) (ac) —H —H

C₃₂H₃₅N₅O₄ 554 [m + H]⁺ 180- 185 0.50 (D) (ad) —H —H

C₃₂H₃₄N₄O₄ 539 [m + H]⁺ 190- 193 0.40 (D) (ae) —CH₃ —CH₃

C₃₂H₃₅N₅O₄ 554 [m + H]⁺ 254- 257 0.50 (C) (af) —H —H

C₃₀H₃₁N₅O₄ 526 [m + H]⁺ 170- 175 0.40 (A) (ag) —H —H

C₃₀H₃₁N₅O₄ 526 [m + H]⁺ 205- 208 0.40 (A) (ah) —H —H—N(Me)—(CO)—(CH₂)₃—NMe₂ C₃₀H₃₂N₄O₄ 511 166- 0.40 [m − H]⁻ 170 (C) (ai)—H —H —N(Me)—(CO)—NH—(CH₂)₃—NMe₂ C₃₀H₃₃N₅O₄ 528 166- 0.30 [m + H]⁺ 170(E) (aj) —H —H —H C₂₃H₁₈N₂O₃ 371 275- 0.80 [m + H]⁺ 280 (C) (ak) —H —H—N(SO₂Me)—CH₃ C₂₅H₂₃N₃O₅S 478 278- 0.70 [m + H]⁺ 282 (C) *Solvents: (A):silica gel, methylene chloride/methanol 9:1 (B): aluminum oxide,methylene chloride/methanol 20:1 (C): silica gel, methylenechloride/methanol/ammonia 9:1:0.1 (D): silica gel, methylenechloride/methanol/ammonia 5:1:0.01 (E): silica gel, methylenechloride/methanol/ammonia 9:1:0.01

The following compound is prepared analogously:

-   (al)    3-Z-(1-cyclohexylamino-1-phenyl-methylene)-6-methoxycarbonyl-2-indolinone

R_(f) value: 0.60 (silica gel, methylene chloride/methanol=9:1)

Melting point: 236-243° C. C₂₃H₂₄N₂O₃

Mass spectrum: m/z=377 [m+H]⁺

Examples (am) to (av)

The following compounds of general formula III are prepared analogouslyto the compounds described in WO 01/27081:

Melting Mass point Example R⁶ Formula spectrum [° C.] R_(f)-value* (am)

C₂₈H₂₈N₄O₃ 467 [m − H]⁻ 275 0.50 (A) (an) —CH₂—NHMe C₂₄H₂₁N₃O₃ 398 2870.70 [m − H]⁻ (A) (ao)

C₂₇H₂₅N₃O₄ 454 [m − H]⁻ 335 0.70 (A) (ap) —N(SO₂Me)—(CH₂)₂—NMe₂C₂₇H₂₈N₄O₅S 519 280 0.70 [m − H]⁻ (A) (aq)

C₂₇H₂₇N₃O₅ 596 [m + Na]⁺ 256-257 0.75 (ar)

C₃₀H₃₁N₅O₄ 526 [m + H]⁺ 346 0.60 (A) (as)

C₂₉H₂₈N₄O₅ 513 [m + H]⁺ 237-238 0.70 (A) (at)

C₃₀H₃₃N₅O₄ 528 [m + H]⁺ 238-240 0.50 (A) (au) —O(CH₂)₂—NMe₂ C₂₆H₂₅N₃O₄444 n.b. 0.35 [m + H]⁺ (B) *Solvents: (A): reversed phase RP8,methanol/brine (5%) = 4:1 (B): silica gel, methylene chloride/methanol4:1

The following compound is prepared analogously:

-   (av)    3-Z-(1-cyclohexylamin-1-phenyl-methylene)-6-carboxy-2-indolinone

Rf value: 0.50 (silica gel, methylene chloride/methanol=9:1)

Melting point: 347-350° C.

C₂₂H₂₂N₂O₃

Mass spectrum: m/z=363 [m+H]⁺

Examples (aw) to (az)

-   (aw)    3-Z-[1-(3-(dimethylaminomethyl)-anilino)-1-(3-(2-carboxy-ethyl)-phenyl)-methylene]-6-methoxycarbonyl-2-indolinone-   (ax)    3-Z-[1-(4-(2-dimethylamino-ethyl)-anilino)-1-(3-(2-carboxy-ethyl)-phenyl)-methylene]-6-methoxycarbonyl-2-indolinon-   (ay)    3-Z-[1-(4-(1-methyl-imidazol-2-yl)-anilino)-1-(3-(2-carboxy-ethyl)-phenyl)-methylene]-6-methoxycarbonyl-2-indolinone-   (az)    3-Z-[1-(4-(dimethylaminomethyl)-anilino)-1-(4-(2-carboxy-ethyl)-phenyl)-methylene]-6-methoxycarbonyl-2-indolinone

Preparation of the Starting Compounds:

(I.1)1-acetyl-3-(1-hydroxy-1-(3-(2-ethoxycarbonyl-ethyl)-phenyl)-methylene)-6-methoxycarbonyl-2-indolinone6.00 g 1-acetyl-6-methoxycarbonyl-2-indolinone, 6.30 g3-(2-ethoxycarbonyl-ethyl)-benzoic acid (preparation analogously toTetrahedron 1997, 53, 7335-7340) and 9.10 g TBTU are dissolved in 80 mlof dimethylformamide, 13.5 ml diisopropylmethylamine and 4.34 g HOBt areadded and the mixture is stirred for 12 hrs at ambient temperature.After this time the solvent is removed, diluted hydrochloric acid isadded and the residue is recrystallized from methylenechloride/methanol.

Yield: 10.6 g (94% of theory)

R_(f) value: 0.50 (silica gel, methylene chloride/methanol=19:1)

Melting point: 80-84° C.

C₂₄H₂₃NO₇

Mass spectrum: m/z=438 [m+H]⁺

The following compounds are prepared analogously:

(I.2)1-acetyl-3-(1-hydroxy-1-(4-(2-methoxycarbonyl-ethyl)-phenyl)-methylene)-6-methoxycarbonyl-2-indolinoneprepared from 1-acetyl-6-methoxycarbonyl-2-indolinone and4-(2-methoxycarbonyl-ethyl)-benzoic acid (preparation analogously toTetrahedron 1997, 53, 7335-7340)

R_(f) value: 0.60 (silica gel, methylene chloride/methanol=19:1)

Melting point: 188-192° C.

C₂₃H₂₁NO₇

Mass spectrum: m/z=422 [m−H]⁻

(II.1)1-acetyl-3-(1-methoxy-1-(3-(2-ethoxycarbonyl-ethyl)-phenyl)-methylene)-6-methoxycarbonyl-2-indolinone7.17 g trimethyloxoniumtetrafluoroborate are slowly added to a solutionof 10.6 g1-acetyl-3-(1-hydroxy-1-(3-(2-ethoxycarbonyl-ethyl)-phenyl)-methylene)-6-methoxycarbonyl-2-indolinone(starting material I.1) and 12.5 ml ethyldiisopropylamine in 100 mlmethylene chloride. After stirring for 4 hrs at ambient temperatureanother 3.50 g trimethyloxoniumtetrafluoroborate are added and themixture is stirred for 12 hrs at ambient temperature. After that timethe mixture is washed twice with water, the organic phase is dried overmagnesium sulphate and the solvent is removed. The residue is purifiedover a silica gel column with methylene chloride/methanol (97:3) aseluant.

Yield: 4.56 g (42% of theory)

R_(f) value: 0.90 (silica gel, methylene chloride/methanol=20:1)

C₂₅H₂₅NO₇

Mass spectrum: m/z=452 [m+H]⁺

The following compounds are prepared analogously:

(II.2)1-acetyl-3-(1-methoxy-1-(4-(2-methoxycarbonyl-ethyl)-phenyl)-methylene)-6-methoxycarbonyl-2-indolinoneprepared from1-acetyl-3-(1-hydroxy-1-(4-(2-methoxycarbonyl-ethyl)-phenyl)-methylene)-6-methoxycarbonyl-2-indolinone(starting material I.2)

R_(f) value: 0.80 (silica gel, methylene chloride/methanol=19:1) Meltingpoint: 112-117° C.

C₂₄H₂₃NO₇

Mass spectrum: m/z=438 [m+H]⁺

(III.1)3-Z-[1-(4-(dimethylaminomethyl)-anilino)-1-(3-(2-ethoxycarbonyl-ethyl)-phenyl)-methylene]-6-methoxycarbonyl-2-indolinone

1.2 g1-acetyl-3-(1-methoxy-1-(3-(2-ethoxycarbonyl-ethyl)-phenyl)-methylene)-6-methoxycarbonyl-2-indolinone(starting material II.1) and 0.32 g 4-(dimethylaminomethyl)-aniline aredissolved in 10 ml of dimethylformamide and stirred for 3 days at 110°C. After cooling the solvent is evaporated, the residue is taken up in 5ml of methanol and 200 mg 20 percent sodiumethylat-solution in ethanolare added. The mixture is stirred for 1.5 hrs at ambient temperature,the solvent is removed and the residue is taken up in water. The aqueousphase is three times extracted with ethyl acetate and the combinedorganic phases are dried over sodium sulphate. After evaporation of thesolvent the residue is purified over a silica gel column with methylenechloride/methanol (9:1) as eluant.

Yield: 0.33 g (35% of theory),

R_(f) value: 0.35 (silica gel, methylene chloride/methanol=9:1)

Melting point: 129-134° C.

C₃₁H₃₃N₃O₅

Mass spectrum: m/z=528 [m+H]⁺

The following compounds are prepared analogously:

(III.2)3-Z-[1-(4-(2-dimethylamino-ethyl)-anilino)-1-(3-(2-ethoxycarbonyl-ethyl)-phenyl)-methylene]-6-methoxycarbonyl-2-indolinone

prepared from1-acetyl-3-(1-methoxy-1-(3-(2-ethoxycarbonyl-ethyl)-phenyl)-methylene)-6-methoxycarbonyl-2-indolinone(starting material II.1)

R_(f) value: 0.30 (silica gel, methylene chloride/methanol=9:1)

Melting point: 174-177° C.

C₃₂H₃₅N₃O₅

Mass spectrum: m/z=542 [m+H]⁺

(III.3)3-Z-[1-(4-(1-methyl-imidazol-2-yl)-anilino)-1-(3-(2-ethoxycarbonyl-ethyl)-phenyl)-methylene]-6-methoxycarbonyl-2-indolinone

prepared from1-acetyl-3-(1-methoxy-1-(3-(2-ethoxycarbonyl-ethyl)-phenyl)-methylene)-6-methoxycarbonyl-2-indolinone(starting material II.1)

R_(f) value: 0.45 (silica gel, methylene chloride/methanol=9:1)

Melting point: 102° C.

C₃₂H₃₀N₄O₅

Mass spectrum: m/z=551 [m+H]⁺

(III.4)3-Z-[1-(4-(dimethylaminomethyl)-anilino)-1-(4-(2-methoxycarbonyl-ethyl)-phenyl)-methylene]-6-methoxycarbonyl-2-indolinone

prepared from1-acetyl-3-(1-methoxy-1-(4-(2-methoxycarbonyl-ethyl)-phenyl)-methylene)-6-methoxycarbonyl-2-indolinone(starting material II.2)

R_(f) value: 0.50 (silica gel, methylene chloride/methanol=9:1)

Melting point: 226-229° C.

C₃₀H₃₁N₃O₅

Mass spectrum: m/z=512 [m−H]⁻

Preparation of the Final Compounds:

The following compounds of general formula IV are prepared analogouslyto the compounds described in WO 01/27081, starting from the abovementioned starting materials:

Melting Starting Mass point Example R³ R⁶ compound Formula spectrum [°C.] R_(f) value* (aw)

—CH₂—NMe₂ III.1 C₂₉H₂₉N₃O₅ 500 [m + H]⁺ 163- 167 0.40 (A) (ax)

—(CH₂)₂—NMe₂ III.2 C₃₀H₃₁N₃O₅ 514 [m + H]⁺ 248- 255 0.35 (A) (ay)

III.3 C₃₀H₂₆N₄O₅ 523 [m + H]⁺ 184- 190 0.35 (A) (az)

—CH₂—NMe₂ III.4 C₂₉H₂₉N₃O₅ 498 [m − H]⁻ 190- 195 0.20 (B) *Solvents:(A): Reversed Phase RP8, methanol/brine (5%) = 4:1 (B): silica gel,methylene chloride/methanol 9:1

Examples (ba) to (cn)

Preparation of the Starting Compounds:

(IV) 3-(1-hydroxy-1-phenyl-methylene)-6-carboxy-2-indolinone 11.0 g1-acetyl-3-(1-methoxy-1-phenyl-methylene)-6-methoxycarbonyl-2-indolinone(preparation described in WO 01/27081) are dissolved in 500 ml ofmethanol and 160 ml of 1N sodium hydroxide solution are added. Themixture is stirred for 1 hr at ambient temperature and for 6 hrs atreflux. After that time another 20 ml of 1N sodium hydroxide solutionare added and the mixture is stirred for another 3 hrs at reflux. 160 mlof 1N hydrochloric acid are added, the resulting residue is filtered offand dried at 100° C. The residue is used without further purification.

Yield: 7.60 g (86% of theory)

(V.1)3-(1-hydroxy-1-phenyl-methylene)-6-(N-ethyl-methylcarbamoyl)-2-indolinone

5.50 g 3-(1-hydroxy-1-phenyl-methylene)-6-carboxy-2-indolinone (startingmaterial IV), 7.54 g TBTU, 3.60 g HOBt and 17.1 ml ethyldiisopropylamineare dissolved in 200 ml of dimethylformamide. 2.70 ml of a 94-percentsolution of N-methyl-ethylamine are added and the mixture is stirred for12 hrs at ambient temperature. After that time the solvent is evaporatedand the residue is purified over a silica gel column with methylenechloride/methanol/ammonia (9:1:0.1) as eluant.

Yield: 6.10 g (97% of theory)

R_(f) value: 0.35 (silica gel, methylenechloride/methanol/ammonia=9:1:0.1)

C₁₉H₁₈N₂O₃

Mass spectrum: m/z=323 [m+H]⁺

The following compound is prepared analogously:

(V.2) 3-(1-hydroxy-1-phenyl-methylene)-6-ethylcarbamoyl-2-indolinone

prepared from 3-(1-hydroxy-1-phenyl-methylene)-6-carboxy-2-indolinone(starting material IV) und ethylamine C₁₈H₁₆N₂O₃

Mass spectrum: m/z=309 [m+H]⁺

Preparation of the Final Compounds:

(ba)3-Z-[1-(4-(2-dimethylamino-ethyl)-anilino)-1-phenyl-methylene]-6-(N-ethyl-methylcarbamoyl)-2-indolinone250 mg3-(1-hydroxy-1-phenyl-methylene)-6-(N-ethyl-methylcarbamoyl)-2-indolinone(starting material V.1) and 382 mg 4-(2-dimethylamino-ethyl)-aniline aredissolved in 3 ml of tetrahydrofuran, 569 ml trimethylsilylimidazole areadded and the mixture is stirred at 170° C. in a microwave oven. Aftercooling the solvent is evaporated and the residue is taken up in water.The residue is filtered off and vacuum-dried at 90° C.

Yield: 0.18 g (50% of theory),

R_(f) value: 0.30 (silica gel, methylenechloride/methanol/ammonia=9:1:0.1)

Melting point: 195-200° C.

C₂₉H₃₂N₄O₂

Mass spectrum: m/z=469 [m+H]⁺

The following compounds of general formula V are prepared analogously tothe above compound (ba), following the procedures described in WO01/27081:

Melting Mass point Example X R⁴ Formula spectrum [° C.] R_(f) value*(bb) —CH₃

C₂₈H₃₀N₄O₂ 455 [m + H]⁺ 239-243 0.35 (A) (bc) —CH₃

C₂₅H₃₀N₄O₂ 419 [m + H]⁺ 267-271 0.35 (B) (bd) —CH₃

C₂₇H₃₄N₄O₂ 447 [m + H]⁺ 133-138 0.30 (B) (be) —CH₃

C₃₁H₃₆N₄O₃ 513 [m + H]⁺ 191-196 0.45 (B) (bf) —CH₃

C₃₃H₃₉N₅O₃ 554 [m + H]⁺ 258-262 0.40 (B) (bg) —CH₃

C₃₃H₃₈N₆O₃ 567 [m + H]⁺ 214-218 0.20 (B) (bh) —CH₃

C₂₅H₂₉N₃O₂ 404 [m + H]⁺ 239-242 0.70 (A) (bi) —CH₃

C₃₁H₃₅N₅O₃ 526 [m + H]⁺ 237-240 0.30 (B) (bj) —CH₃

C₃₀H₃₄N₄O₂ 483 [m + H]⁺ 105-108 0.40 (B) (bk) —CH₃

C₃₀H₃₃N₅O₃ 512 [m + H]⁺ 208-211 0.40 (B) (bl) —CH₃

C₃₀H₃₅N₅O₄S 562 [m + H]⁺ 197-201 0.40 (B) (bm) —CH₃

C₂₅H₂₃N₃O₂ 398 [m + H]⁺ 296-301 0.40 (B) (bn) —CH₃

C₂₈H₃₀N₄O₂ 455 [m + H]⁺ 243-247 0.30 (A) (bo) —H

C₂₈H₃₀N₄O₂ 455 [m + H]⁺ 328-332 0.30 (A) (bp) —CH₃

C₃₂H₃₇N₅O₃ 540 [m + H]⁺ 224-228 0.25 (A) (bq) —CH₃

C₂₇H₂₈N₄O₄S 505 [m + H]⁺ 265-269 0.40 (B) (br) —CH₃

C₂₇H₂₅N₃O₄ 456 [m + H]⁺ 254-257 0.60 (B) (bs) —CH₃

C₂₆H₂₃N₃O₄ 442 [m + H]⁺ 316-321 0.10 (B) (bt) —CH₃

C₃₀H₃₃N₅O₅S 576 [m + H]⁺ 258-262 0.35 (B) (bu) —H

C₂₈H₃₀N₄O₃ 471 [m + H]⁺ 308-311 0.35 (B) (bv) —H

C₃₂H₃₆N₆O₃ 553 [m + H]⁺ 279-283 0.60 (C) (bw) —H

C₂₉H₃₃N₅O₄S 548 [m + H]⁺ 213-217 0.35 (B) (bx) —CH₃

C₂₉H₃₂N₄O₃ 485 [m + H]⁺ 218-222 0.40 (A) (by) —H

C₂₉H₃₁N₅O₃ 498 [m + H]⁺ 130-134 0.35 (D) (bz) —H

C₂₇H₂₈N₄O₂ 441 [m + H]⁺ 341-344 0.45 (D) (ca) —H

C₃₀H₃₃N₅O₃ 512 [m + H]⁺ 266-270 0.40 (D) (cb) —H

C₃₁H₃₅N₅O₃ 526 [m + H]⁺ 198-202 0.40 (D) (cc) —CH₃

C₂₆H₂₄N₄O₃ 441 [m + H]⁺ 290-295 0.25 (B) (cd) —CH₃

C₃₂H₃₇N₅O₃ 540 [m + H]⁺ 120-126 0.40 (B) (ce) —CH₃

C₃₁H₃₃N₅O₃ 524 [m + H]⁺ 100-105 0.50 (B) (cf) —H

C₃₀H₃₁N₅O₃ 510 [m + H]⁺ 288-292 0.40 (A) (cg) —CH₃

C₃₂H₃₅N₅O₃ 538 [m + H]⁺ 157-163 0.30 (B) (ch) —CH₃

C₃₂H₃₇N₅O₃ 540 [m + H]⁺ 162-169 0.20 (B) (ci) —CH₂CH₃

C₃₄H₄₀N₆O₃ 581 [m + H]⁺ 195-198 0.50 (E) (cj) —CH₃

C₃₂H₃₅N₅O₃ 538 [m + H]⁺ 238-242 0.35 (B) (ck) —H

C₃₁H₃₃N₅O₃ 524 [m + H]⁺ 127-130 0.50 (D) (cl) —H

C₃₁H₃₅N₅O₃ 526 [m + H]⁺ 250-253 0.40 (D) (cm) —H

C₃₂H₃₅N₅O₃ 524 [m + H]⁺ 217-220 0.40 (D) (cn) —H

C₂₉H₃₃N₅O₄S 560 [m − H]⁻ 171-175 0.45 (D) *Solvents: (A): silica gel,methylene chloride/methanol 9:1 (B): silica gel, methylenechloride/methanol/ammonia 9:1:0.1 (C): aluminum oxide, methylenechloride/methanol 9:1 (D): aluminum oxide, methylene chloride/methanol19:1 (E): Reversed Phase RP8, acetonitrile/water/trifluoroacetic acid =1:1:0.01

Examples (co) to (cq)

Preparation of the Starting Compounds:

(VI) 1-acetyl-3-(1-ethoxy-methylene)-6-methoxycarbonyl-2-indolinone

8.00 g 1-acetyl-6-methoxycarbonyl-2-indolinone and 17.2 ml triethylorthoformate are dissolved in 70 ml of acetic anhydride and stirred for5.5 hrs at 110° C. After cooling the residue is filtered off, washedwith ether and vacuum-dried at 100° C.

Yield: 8.80 g (89% of theory)

R_(f) value: 0.35 (silica gel, petrol ether/methylenechloride/ethylacetate=5:4:1)

Melting point: 187-189° C.

C₁₅H₁₅NO₅

Mass spectrum: m/z=290 [m+H]⁺

Preparation of the Final Compounds:

The following compounds of general formula VI are prepared analogouslyto the compounds described in WO 01/27081:

Melting Mass point R_(f) Example R⁶ Formula spectrum [° C.] value* (co)—NMe—(CO)—CH₂—NMe₂ C₂₂H₂₄N₄O₄ 409 250-255 0.40 [m + H]⁺ (A) (cp)—CH₂—NMe₂ C₂₀H₂₁N₃O₃ 352 234-238 035 [m + H]⁺ (A) (cq)

C₂₅H₂₉N₅O₄ 464 [m + H]⁺ 203-207 0.45 (A) *Solvents: (A): silica gel,methylene chloride/methanol/ammonia 9:1:0.1

Examples (cr) to (cu)

Preparation of the Starting Compounds:

(VII) 3-(1-hydroxy-methylene)-6-carboxy-2-indolinone

5.00 g 1-acetyl-3-(1-ethoxy-methylene)-6-methoxycarbonyl-2-indolinone(starting material VI) are dissolved in 150 ml of methanol and 86.4 mlof 1N sodium hydroxide solution are added. The mixture is refluxed for8.5 hrs. After that time 86.4 ml of 1N hydrochloric acid are added. Theresidue is filtered off and dried at 90° C.

Yield: 2.50 g (71% of theory)

C₁₀H₇NO₄

Mass spectrum: m/z=206 [m+H]⁺

(VIII) 3-(1-hydroxy-methylene)-6-ethylcarbamoyl-2-indolinone 400 mg3-(1-hydroxy-methylene)-6-carboxy-2-indolinone (starting material VII),689 mg TBTU, 291 mg HOBt and 1.35 ml triethylamine are dissolved in 20ml of dimethylformamide. At 0° C. 1.95 ml of a 2M ethylamine-solution inTHF are added and the mixture is stirred for additional 12 hrs atambient temperature. After that time the solvent is evaporated and theresidue is purified over a silica gel column with methylenechloride/ethanol/acetic acid (5:1:0.01) as eluant.

Yield: 160 mg (35% of theory)

R_(f) value: 0.20 (silica gel, methylene chloride/ethanol/aceticacid=5:1:0.01)

Melting point: 146-150° C.

C₁₂H₁₂N₂O₃

Mass spectrum: m/z=233 [m+H]⁺

Preparation of the Final Compounds:

(cr)3-Z-[1-(4-(N-(4-methyl-piperazin-1-yl-methylcarbonyl)-N-methyl-amino)-anilino)-methylene]-6-ethylcarbamoyl-2-indolinone

160 mg 3-(1-hydroxy-methylene)-6-ethylcarbamoyl-2-indolinone (startingmaterial VIII) and 543 mgN-[(4-methyl-piperazin-1-yl)-methylcarbonyl]-N-methyl-p-phenylendiamineare dissolved in 3 ml of tetrahydrofuran, 506 ml trimethylsilylimidazoleare added and the mixture is stirred for 25 minutes at 170° C. in amicrowave oven. After cooling the solvent is evaporated and the residueis purified over an aluminum oxide column (activity 2-3) with methylenechloride/ethanol (19:1) as eluant. The residue is recrystallized fromether and vacuum-dried at 80° C.

Yield: 0.17 g (52% of theory),

R_(f) value: 0.60 (aluminum oxide, methylene chloride/methanol=9:1)

Melting point: 255-260° C.

C₂₆H₃₂N₆O₃

Mass spectrum: m/z=477 [m+H]⁺

The following compounds of general formula VII are prepared analogouslyto the above compound (ct), following the procedures described in WO01/27081:

Melting Mass point R_(f) Example X R⁴ Formula spectrum [° C.] value*(cs) —H

C₂₃H₂₇N₅O₃ 422 [m + H]⁺ 280-283 0.70 (A) (ct) —H

C₂₄H₂₈N₄O₂ 405 [m + H]⁺ 245-248 0.80 (A) (cu) —H

C₂₅H₃₁N₅O₃ 450 [m + H]⁺ 130 0.40 (B) *Solvents: (A): aluminum oxide,methylene chloride/methanol 9:1 (B): silica gel, methylenechloride/ethanol/ammonia 5:2:0.01

Tautomers, stereoisomers or physiologically acceptable salts of thesecompounds are also contemplated within the scope of the presentinvention, and may be obtained using the methods described in WO01/27081, the content of which is herein incorporated by reference.

A particularly preferred compound is the monoethanesulphonate salt of3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone,disclosed for example in WO 04/13099, the content of which isincorporated herein by reference.

The metabolites of the compound3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-monoethanesulphonateand the prodrugs of this compound or of these metabolites obtained via,for example, chemical or non-chemical derivatization of the entiremolecule or of one or more chemical groups on the molecule, are alsocontemplated compounds within the meaning of the present invention. Inthis matter, reference is made to WO 04/13099, which describesmetabolites and prodrugs of the compound3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-monoethanesulphonate.

The following list of specific compounds is illustrative of the presentinvention, without constituting any limitation of its scope:

-   (1) 3-Z-(1-anilino-1-phenyl-methylene)-6-ethoxycarbonyl-2-indolinone-   (2)    3-Z-[1-(4-nitro-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (3)    3-Z-[1-(4-fluoro-anilino)-1-phenyl-methylene]-6-ethoxy-carbonyl-2-indolinone-   (4)    3-Z-[1-(4-chloro-anilino)-1-phenyl-methylene]-6-ethoxy-carbonyl-2-indolinone-   (5)    3-Z-[1-(4-iodo-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (6)    3-Z-[1-(4-cyano-anilino)-1-phenyl-methylene]-6-ethoxy-carbonyl-2-indolinone-   (7)    3-Z-[1-(4-methoxy-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (8)    3-Z-[1-(4-ethoxy-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (9)    3-Z-[1-(4-trifluoromethyl-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (10)    3-Z-[1-(4-methyl-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (11)    3-Z-[1-(4-methylmercapto-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (12)    3-Z-[1-(4-aminomethyl-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (13)    3-Z-[1-(4-(isopropylaminomethyl)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (14)    3-Z-[1-(4-(anilinomethyl)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (15)    3-Z-[1-(4-(propylaminomethyl)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (16)    3-Z-[1-(4-(butylaminomethyl)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (17)    3-Z-[1-(4-(isobutylaminomethyl)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (18)    3-Z-[1-(4-(cyclohexylaminomethyl)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (19)    3-Z-[1-(4-(benzylaminomethyl)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (20)    3-Z-[1-(4-((N-ethyl-N-methyl-amino)-methyl)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (21)    3-Z-[1-(4-((N-methyl-N-propyl-amino)-methyl)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (22)    3-Z-[1-(4-((N-isopropyl-N-methyl-amino)-methyl)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (23)    3-Z-[1-(4-((N-ethyl-N-propyl-amino)-methyl)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (24)    3-Z-[1-(4-((N-ethyl-N-isopropyl-amino)-methyl)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (25)    3-Z-[1-(4-(dipropylaminomethyl)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (26)    3-Z-[1-(4-(diisopropylaminomethyl)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (27)    3-Z-[1-(4-((N-benzyl-N-ethyl-amino)-methyl)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (28)    3-Z-[1-(4-(dibenzylaminomethyl)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (29)    3-Z-[1-(4-(3,6-dihydro-2H-pyridin-1-yl-methyl)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (30)    3-Z-[1-(4-(3,5-dimethyl-piperidin-1-yl-methyl)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (31)    3-Z-[1-(4-(azepan-1-yl-methyl)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (32)    3-Z-[1-(4-(piperazin-1-yl-methyl)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (33)    3-Z-[1-(4-(morpholin-4-yl-methyl)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (34)    3-Z-[1-(4-(thiomorpholin-4-yl-methyl)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (35)    3-Z-[1-(4-(1-oxo-thiomorpholin-4-yl-methyl)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (36)    3-Z-[1-(4-(1,1-dioxo-thiomorpholin-4-yl-methyl)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (37)    3-Z-[1-(4-(acetylamino-methyl)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (38)    3-Z-[1-(4-(2-amino-ethyl)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (39)    3-Z-[1-(4-(2-methylamino-ethyl)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (40)    3-Z-[1-(4-(2-ethylamino-ethyl)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (41)    3-Z-[1-(4-(2-diethylamino-ethyl)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (42)    3-Z-[1-(4-(2-piperidin-1-yl-ethyl)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (43)    3-Z-[1-(4-(2-acetylamino-ethyl)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (44)    3-Z-[1-(4-(3-amino-propyl)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (45)    3-Z-[1-(4-(3-dimethylamino-propyl)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (46)    3-Z-[1-(4-(N-aminomethylcarbonyl-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (47)    3-Z-[1-(4-(N-methylaminomethylcarbonyl-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (48)    3-Z-[1-(4-(N-ethylaminomethylcarbonyl-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (49)    3-Z-[1-(4-(N-diethylaminomethylcarbonyl-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-indolinone-   (50)    3-Z-[1-(4-(N-(piperidin-1-yl-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-indolinone-   (51)    3-Z-[1-(4-(N-(morpholin-4-yl-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (52)    3-Z-[1-(4-(N-(piperazin-1-yl-methylcarbonyl)-N-methyl-amino]-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-indolinone-   (53)    3-Z-[1-(4-(N-(2-amino-ethylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (54)    3-Z-[1-(4-(N-(2-methylamino-ethylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-indolinone-   (55)    3-Z-[1-(4-(N-(2-diethylamino-ethylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-indolinone-   (56)    3-Z-[1-(4-(N-acetyl-N-(2-aminoethyl)-amino)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (57)    3-Z-[1-(4-(N-acetyl-N-(2-methylamino-ethyl)-amino)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (58)    3-Z-[1-(4-(N-acetyl-N-(2-methylamino-propyl)-amino)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (59)    3-Z-[1-(4-(N-acetyl-N-(2-piperidin-1-yl-ethyl)-amino)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (60)    3-Z-[1-(4-(N-acetyl-N-(aminocarbonylmethyl)-amino)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (61)    3-Z-[1-(4-(N-acetyl-N-(dimethylaminocarbonylmethyl)-amino)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-indolinone-   (62)    3-Z-[1-(4-(N-acetyl-N-(piperidin-1-yl-carbonylmethyl)-amino)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-indolinone-   (63)    3-Z-[1-(4-(N-methyl-N-(aminocarbonyl)-amino)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (64)    3-Z-[1-(4-(N-methyl-N-(methylaminocarbonyl)-amino)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (65)    3-Z-[1-(4-(N-methyl-N-(dimethylaminocarbonyl)-amino)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (66)    3-Z-[1-(4-(N-methyl-N-(piperidin-1-yl-carbonyl)-amino)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (67)    3-Z-[1-(4-(N-(2-aminoethyl)-N-methylsulphonyl-amino)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (68)    3-Z-[1-(4-(N-(2-methylamino-ethyl)-N-methylsulphonyl-amino)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (69)    3-Z-[1-(4-(N-(2-ethylamino-ethyl)-N-methylsulphonyl-amino)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (70)    3-Z-[1-(4-(N-(2-diethylamino-ethyl)-N-methylsulphonyl-amino)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (71)    3-Z-[1-(4-(N-(2-pyrrolidin-1-yl-ethyl)-N-methylsulphonyl-amino)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (72)    3-Z-[1-(4-(N-(2-piperidin-1-yl-ethyl)-N-methylsulphonyl-amino)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (73)    3-Z-[1-(4-(N-(2-piperazin-1-yl-ethyl)-N-methylsulphonyl-amino)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (74)    3-Z-[1-(4-(N-(2-(morpholin-4-yl)-ethyl)-N-methylsulphonyl-amino)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (75)    3-Z-[1-(4-(N-(aminocarbonylmethyl)-N-methylsulphonyl-amino)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (76)    3-Z-[1-(4-(N-(methylaminocarbonylmethyl)-N-methylsulphonyl-amino)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (77)    3-Z-[1-(4-(N-(ethylaminocarbonylmethyl)-N-methylsulphonyl-amino)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (78)    3-Z-[1-(4-(N—(N-(2-dimethylamino-ethyl)-N-methyl-amino)-carbonylmethyl)-N-methylsulphonyl-amino)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (79)    3-Z-[1-(4-(N-(diethylaminocarbonylmethyl)-N-methylsulphonyl-amino)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (80) 3-Z-[1-(4-(N-(pyrrolidin-1-yl-carbonylmethyl)-N-m    sulphonyl-amino)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (81)    3-Z-[1-(4-(N-(piperidin-1-yl-carbonylmethyl)-N-methylsulphonyl-amino)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (82)    3-Z-[1-(4-(N-(piperazin-1-yl-carbonylmethyl)-N-methylsulphonyl-amino)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (83)    3-Z-[1-(4-(N-((morpholin-4-yl)-carbonylmethyl)-N-methylsulphonyl-amino)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (84)    3-Z-[1-(4-(2-dimethylamino-ethoxy)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (85)    3-Z-[1-(4-(3-dimethylamino-propoxy)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (86)    3-Z-[1-(4-(aminocarbonylmethyl)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (87)    3-Z-[1-(4-(2-aminocarbonyl-ethyl)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (88)    3-Z-[1-(4-(pyridin-2-yl)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (89)    3-Z-[1-(4-(pyridine-3-yl)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (90)    3-Z-[1-(4-(pyridin-4-yl)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (91)    3-Z-[1-(4-(N-acetyl-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (92)    3-Z-[1-(4-(N-ethylcarbonyl-N-(dimethylaminocarbonyl-methyl)-amino)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (93)    3-Z-[1-(carbamoylmethyl-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (94)    3-Z-[1-(4-dimethylcarbamoylmethyl-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (95)    3-Z-[1-(4-(piperidin-1-yl-methyl)-anilino)-methylene]-6-ethoxycarbonyl-2-indolinone-   (96)    3-Z-[1-(4-(piperidin-1-yl-methyl)-anilino)-propylidene]-6-ethoxycarbonyl-2-indolinone-   (97)    3-Z-[1-(4-(piperidin-1-yl-methyl)-anilino)-butylidene]-6-ethoxycarbonyl-2-indolinone-   (98)    3-Z-[1-(4-(N-(3-dimethylamino-propyl)-N-acetyl-amino)-anilino)-methylene]-6-ethoxycarbonyl-2-indolinone-   (99)    3-Z-[1-(4-(N-(3-dimethylamino-propyl)-N-acetyl-amino)-anilino)-ethylidene]-6-ethoxycarbonyl-2-indolinone-   (100)    3-Z-[1-(4-(N-(3-dimethylamino-propyl)-N-acetyl-amino)-anilino)-propylidene]-6-ethoxycarbonyl-2-indolinone-   (101)    3-Z-[1-(4-(N-(3-dimethylamino-propyl)-N-acetyl-amino)-anilino)-butylidene]-6-ethoxycarbonyl-2-indolinone-   (102)    3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-methylsulphonyl-amino)-anilino)-methylene]-6-ethoxycarbonyl-2-indolinone-   (103)    3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-methylsulphonyl-amino)-anilino)-propylidene]-6-ethoxycarbonyl-2-indolinone-   (104)    3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-methylsulphonyl-amino)-anilino)-butylidene]-6-ethoxycarbonyl-2-indolinone-   (105)    3-Z-[1-(4-tetrazol-5-yl-anilino)-methylene]-6-ethoxycarbonyl-2-indolinone-   (106)    3-Z-[1-(4-tetrazol-5-yl-anilino)-ethylidene]-6-ethoxy-carbonyl-2-indolinone-   (107)    3-Z-[1-(4-tetrazol-5-yl-anilino)-propylidene]-6-ethoxycarbonyl-2-indolinone-   (108)    3-Z-[1-(4-tetrazol-5-yl-anilino)-butylidene]-6-ethoxycarbonyl-2-indolinone-   (109)    3-Z-[1-(4-carboxy-anilino)-methylene]-6-ethoxycarbonyl-2-indolinone-   (110)    3-Z-[1-(4-carboxy-anilino)-propylidene]-6-ethoxycarbonyl-2-indolinone-   (111)    3-Z-[1-(4-carboxy-anilino)-butylidene]-6-ethoxycarbonyl-2-indolinone-   (112)    3-Z-[1-(4-(N-(3-dimethylamino-propionyl)-N-dimethylaminocarbonylmethyl-amino)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (113)    3-Z-[1-(4-(N-(4-dimethylamino-butyryl)-N-dimethylaminocarbonylmethyl-amino)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (114)    3-Z-[1-(4-(N-dimethylaminocarbonylmethyl-N-(2-dimethylamino-ethylsulphonyl)-amino)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (115)    3-Z-[1-(4-(N-dimethylaminocarbonylmethyl-N-(3-dimethylamino-propylsulphonyl)-amino)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (116)    3-Z-[1-(4-((2-hydroxy-ethyl)-amino-methyl)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (117)    3-Z-[1-(4-((2-methoxy-ethyl)-amino-methyl)-anilino-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (118) 3-Z-[1-(4-((2-dimethylamino-ethyl)-amino-methyl)    anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (119)    3-Z-[1-(4-((3-dimethylamino-propyl)-amino-methyl)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (120)    3-Z-[1-(4-((N-tert.butoxycarbonyl-2-amino-ethyl)-amino-methyl)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (121)    3-Z-[1-(4-((N-tert.butoxycarbonyl-3-amino-propyl)-amino-methyl)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (122)    3-Z-[1-(4-((2-amino-ethyl)-amino-methyl)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (123)    3-Z-[1-(4-((3-amino-propyl)-amino-methyl)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (124)    3-Z-[1-(4-((2-acetylamino-ethyl)-amino-methyl)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (125)    3-Z-[1-(4-((3-acetylamino-propyl)-amino-methyl)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (126)    3-Z-[1-(4-((2-methylsulphonylamino-ethyl)-amino-methyl)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-indolinone-   (127)    3-Z-[1-(4-((3-methylsulphonylamino-propyl)-amino-methyl)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-indolinone-   (128)    3-Z-[l-(4-(N—(N-tert.butoxycarbonyl-2-amino-ethyl)-N-methyl-amino-methyl)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (129)    3-Z-[1-(4-(N-(2-amino-ethyl)-N-methyl-amino-methyl)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (130)    3-Z-[1-(4-(N-(2-acetylamino-ethyl)-N-methyl-amino-methyl)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-indolinone-   (131)    3-Z-[1-(4-(N-(2-methylsulphonylamino-ethyl)-N-methyl)-amino-methyl)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (132)    3-Z-[1-(4-(carboxymethyl-amino-methyl)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (133)    3-Z-[1-(4-(ethoxycarbonylmethyl-amino-methyl)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (134)    3-Z-[1-(4-(carbamoylmethyl-amino-methyl)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (135)    3-Z-[1-(4-(dimethylcarbamoyl-methyl-amino-methyl)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (136)    3-Z-[1-(4-(methylcarbamoyl-methyl-amino-methyl)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (137)    3-Z-[1-(4-(N-dimethylaminomethylcarbonyl-N-methyl-amino)-3-amino-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (138)    3-Z-[1-(4-(N-dimethylaminomethylcarbonyl-N-methyl-amino)-3-nitro-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (139)    3-Z-[1-(4-(N-dimethylaminomethylcarbonyl-N-methyl-amino)-3-acetylamino-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (140)    3-Z-[1-(4-(N-dimethylaminomethylcarbonyl-N-methyl-amino)-3-methylsulphonylamino-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (141)    3-Z-[1-(4-(N-dimethylaminomethylcarbonyl-N-methyl-amino)-3-cyano-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (142)    3-Z-[1-(4-(N-dimethylaminomethylcarbonyl-N-methyl-amino)-3-hydroxy-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (143)    3-Z-[1-(4-(N-dimethylaminomethylcarbonyl-N-methyl-amino)-3-methoxy-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (144)    3-Z-[1-(4-(N-dimethylaminomethylcarbonyl-N-methyl-amino)-3-ethoxycarbonyl-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (145)    3-Z-[1-(4-(N-dimethylaminomethylcarbonyl-N-methyl-amino)-3-carboxy-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (146)    3-Z-[1-(4-(N-dimethylaminomethylcarbonyl-N-methyl-amino)-3-carbamoyl-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (147)    3-Z-[1-(4-(N-dimethylaminomethylcarbonyl-N-methyl-amino)-3-chloro-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (148)    3-Z-[1-(4-(N-dimethylaminomethylcarbonyl-N-methyl-amino)-3-fluoro-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (149)    3-Z-[1-(4-(N-dimethylaminomethylcarbonyl-N-methyl-amino)-3-bromo-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (150) 3-Z-[1-(4-(N-dimethylaminomethylcarbonyl-N-met    amino)-3-methyl-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (151)    3-Z-[1-(4-(N-dimethylaminomethylcarbonyl-N-methyl-amino)-3-trifluoromethyl-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (152)    3-Z-[1-(4-(N-dimethylaminomethylcarbonyl-N-methyl-amino)-3,5-dibromo-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (153)    3-Z-[1-(4-(N-dimethylaminomethylcarbonyl-N-methyl-amino)-3,5-dichloro-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (154)    3-Z-[1-(4-(dimethylaminomethyl)-3-amino-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (155)    3-Z-[1-(4-(dimethylaminomethyl)-3-nitro-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (156)    3-Z-[1-(4-(dimethylaminomethyl)-3-acetylamino-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (157)    3-Z-[1-(4-(dimethylaminomethyl)-3-(methylsulphonylamino)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (158)    3-Z-[1-(4-(dimethylaminomethyl)-3-cyano-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (159)    3-Z-[1-(4-(dimethylaminomethyl)-3-hydroxy-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (160)    3-Z-[1-(4-(dimethylaminomethyl)-3-methoxy-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (161)    3-Z-[1-(4-(dimethylaminomethyl)-3-(ethoxycarbonyl)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (162)    3-Z-[1-(4-(dimethylaminomethyl)-3-carboxy-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (163)    3-Z-[1-(4-(dimethylaminomethyl)-3-carbamoyl-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (164)    3-Z-[1-(4-(dimethylaminomethyl)-3-chloro-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (165)    3-Z-[1-(4-(dimethylaminomethyl)-3-fluoro-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (166)    3-Z-[1-(4-(dimethylaminomethyl)-3-bromo-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (167)    3-Z-[1-(4-(dimethylaminomethyl)-3-methyl-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (168)    3-Z-[1-(4-(dimethylaminomethyl)-3-trifluoromethyl-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (169)    3-Z-[1-(4-(dimethylaminomethyl)-3,5-dibromo-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (170)    3-Z-[1-(4-(dimethylaminomethyl)-3,5-dichloro-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (171)    3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (172)    3-Z-[1-(4-(N-(imidazo-1-yl-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (173)    3-Z-[1-(4-(N-(phthalimido-2-yl-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (174)    3-Z-[1-(4-(N-aminomethylcarbonyl-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (175)    3-Z-[1-(4-(N-acetylaminomethylcarbonyl-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (176)    3-Z-[1-(4-(N-methylsulphonylaminomethylcarbonyl-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (177)    3-Z-[1-(4-(N—((N-(2-methoxyethyl)-N-methyl-amino)-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (178)    3-Z-[1-(4-(N—((N-(2-dimethylaminoethyl)-N-methyl-amino)-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (179)    3-Z-[1-(4-(N-((di-(2-hydroxyethyl)-amino)-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (180)    3-Z-[1-(4-(N-dimethylaminomethylcarbonyl-N-methyl-amino)-anilino)-methylene]-6-ethoxycarbonyl-2-indolinone-   (181)    3-Z-[1-(4-(N-dimethylaminomethylcarbonyl-N-methyl-amino)-anilino)-ethylidene]-6-ethoxycarbonyl-2-indolinone-   (182)    3-Z-[1-(4-(N-dimethylaminomethylcarbonyl-N-methyl-amino)-anilino)-propylidene]-6-ethoxycarbonyl-2-indolinone-   (183)    3-Z-[1-(4-(N-dimethylaminomethylcarbonyl-N-methyl-amino)-anilino)-butylidene]-6-ethoxycarbonyl-2-indolinone-   (184)    3-Z-[1-(4-(dimethylaminomethyl)-anilino)-methylene]-6-ethoxycarbonyl-2-indolinone-   (185)    3-Z-[1-(4-(dimethylaminomethyl)-anilino)-ethylidene]-6-ethoxycarbonyl-2-indolinone-   (186)    3-Z-[1-(4-(dimethylaminomethyl)-anilino)-propylidene]-6-ethoxycarbonyl-2-indolinone-   (187)    3-Z-[1-(4-(dimethylaminomethyl)-anilino)-butylidene]-6-ethoxycarbonyl-2-indolinone-   (188)    3-Z-[1-(4-(N-dimethylaminocarbonylmethyl-amino)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (189)    3-Z-[1-(4-(N-(3-dimethylamino-propyl)-N-acetyl-amino)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (190)    3-Z-[1-(4-((imidazolidin-2,4-dion-5-ylidene)-methyl)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (191)    3-Z-[1-(4-(N-((2-dimethylamino-ethyl)-carbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (192)    3-Z-[1-(4-(N-tert.butoxycarbonyl-aminomethyl)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (193)    3-Z-[1-(4-(2-oxo-pyrrolidin-1-yl-methyl)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (194)    3-Z-[1-(4-(N-aminocarbonylmethyl-N-methylsulphonyl-amino)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (195)    3-Z-[1-(4-(N-cyanomethyl-N-methylsulphonyl-amino)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (196)    3-Z-[1-(4-(2-(imidazol-4-yl)-ethyl)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (197)    3-Z-[1-(4-((2-(N-benzyl-N-methyl-amino)-ethyl)-N-methylsulphonyl-amino)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (198)    3-Z-[1-(4-cyclohexylamino-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (199)    3-Z-[1-(4-(imidazol-1-yl-methyl)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (200)    3-Z-[1-(4-(imidazol-1-yl-methyl)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (201)    3-Z-[1-(N-methyl-piperidine-4-yl-amino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (202)    3-Z-[1-(4-(imidazol-4-yl-methyl)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (203)    3-Z-[1-(4-((4-hydroxy-piperidin-1-yl)-methyl)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (204)    3-Z-[1-(4-((4-methoxy-piperidin-1-yl)-methyl)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (205)    3-Z-[1-(4-benzyl-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (206)    3-Z-[1-(4-(N-(3-trifluoroacetylamino-propyl)-N-methylsulphonyl-amino)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (207)    3-Z-[1-(4-(4-tert.butoxycarbonyl-piperazin-1-yl-methyl)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (208)    3-Z-[1-(4-(1-methyl-imidazol-2-yl)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (209)    3-Z-[1-(4-(1-methyl-imidazol-2-yl)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (210)    3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-methylsulphonyl-amino)-3-amino-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (211)    3-Z-[1-(4-((3-(N-benzyl-N-methyl-amino)-propyl)-N-methylsulphonyl-amino)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (212)    3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-acetyl-amino)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (213)    3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-butyryl-amino)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (214)    3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-isobutyryl-amino)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (215)    3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-benzoyl-amino)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (216)    3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-acetyl-amino)-3-amino-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (217)    3-Z-[1-(4-(4-hydroxymethyl-piperidin-1-yl-methyl)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (218)    3-Z-[1-(4-(2-(4-hydroxy-piperidin-1-yl)-ethyl)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (219)    3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-propylsulphonyl-amino)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (220)    3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-butylsulphonyl-amino)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (221)    3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-phenylsulphonyl-amino)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (222)    3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-benzylsulphonyl-amino)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (223)    3-Z-[1-(4-((imidazolidin-2,4-dion-5-yl)-methyl)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (224)    3-Z-[1-(4-((3-hydroxy-pyrrolidin-1-yl)-methyl)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (225)    3-Z-[1-(4-(cyclohexylyl-methyl)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (226)    3-Z-[1-(4-(cyclohexyl-carbonyl)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (227)    3-Z-[1-(4-diethylaminomethyl-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (228)    3-Z-[1-(4-(N-(n-hexyl)-N-methyl-aminomethyl)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (229)    3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-(furan-2-carbonyl)-amino)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (230)    3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-(2-methoxy-benzoyl)-amino)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (231)    3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-(pyridine-3-carbonyl)-amino)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (232)    3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-(phenyl-acetyl)-amino)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (233)    3-Z-[1-(4-(imidazol-2-yl)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (234)    3-Z-[1-(4-(1-ethyl-imidazol-2-yl)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (235)    3-Z-[1-(4-(1-benzyl-imidazol-2-yl)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (236)    3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-isopropylsulphonyl-amino)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (237)    3-Z-[1-(4-(N-((4-benzyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (238)    3-Z-[1-(4-(N-(pyrrolidin-1-yl-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (239)    3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-acetyl-amino)-3-bromo-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (240)    3-Z-[1-(4-(5-methyl-imidazol-4-yl)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (241)    3-Z-[1-(4-(N-((2-dimethylamino-ethyl)-carbonyl)-N-isopropyl-amino)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (242)    3-Z-[1-(4-(N-((2-dimethylamino-ethyl)-carbonyl)-N-benzyl-amino)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (243)    3-Z-[1-(4-(N-butyl-N-tert.butoxycarbonyl-aminomethyl)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (244)    3-Z-[1-(4-(N—((N-aminocarbonylmethyl-N-methyl-amino)-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (245)    3-Z-[1-(4-(N—((N-benzyl-N-methyl-amino)-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (246)    3-Z-[1-(4-(N-(di-(2-methoxyethyl)-amino-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (247)    3-Z-[1-(4-(N-((2-(4-tert.butoxycarbonyl-piperazin-1-yl)-ethyl)-carbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (248)    3-Z-[1-(4-(N-((2-(piperidin-1-yl)-ethyl)-carbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (249)    3-Z-[1-(4-(N-((2-(N-benzyl-N-methyl-amino)-ethyl)-carbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (250)    3-Z-[1-(4-(N-dimethylaminomethylcarbonyl-N-isopropyl-amino)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (251)    3-Z-[1-(4-(N-(piperidin-1-yl-methylcarbonyl)-N-isopropyl-amino)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (252)    3-Z-[1-(4-(N-((4-tert.butoxycarbonyl-piperazin-1-yl)-methylcarbonyl)-N-isopropyl-amino)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (253)    3-Z-[1-(4-(N—((N-benzyl-N-methyl-amino)-methylcarbonyl)-N-benzyl-amino)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (254)    3-Z-[1-(4-(N-dimethylaminomethylcarbonyl-N-benzyl-amino)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (255)    3-Z-[1-(4-(N-(piperidin-1-yl-methylcarbonyl)-N-benzyl-amino)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (256)    3-Z-[1-(4-(1,2,4-triazol-2-yl-methyl)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (257)    3-Z-[1-(4-(1,2,3-triazol-2-yl-methyl)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (258)    3-Z-[1-(4-(1,2,3-triazol-1-yl-methyl)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (259)    3-Z-[1-(4-((N-aminocarbonylmethyl-N-methyl-amino)-methyl)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (260)    3-Z-[1-(4-((di-(2-methoxy-ethyl)-amino)-methyl)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (261)    3-Z-[1-(4-((di-(2-hydroxy-ethyl)-amino)-methyl)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (262)    3-Z-[1-(4-((N-ethoxycarbonylmethyl-N-methyl-amino)-methyl)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (263)    3-Z-[1-(4-(azetidin-1-yl-methyl)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (264)    3-Z-[1-(4-(N-propyl-N-tert.butoxycarbonyl-aminomethyl)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (265)    3-Z-[1-(4-((N-(2-(2-methoxy-ethoxy)-ethyl)-N-methyl-amino)-methyl)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (266)    3-Z-[1-(4-((N-(tert.butoxycarbonyl-3-amino-propyl)-N-methyl-amino)-methyl)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (267)    3-Z-[1-(4-((N-(methylcarbamoyl-methyl)-N-methyl-amino)-methyl)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (268)    3-Z-[1-(4-((N-(dimethylcarbamoyl-methyl)-N-methyl-amino)-methyl)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (269)    3-Z-[1-(4-((N-propyl-N-methyl-amino)-methyl)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (270)    3-Z-[1-(4-((N-(2-dimethylamino-ethyl)-N-methyl-amino)-methyl)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (271)    3-Z-[1-(4-((N-(3-dimethylamino-propyl)-N-methyl-amino)-methyl)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (272)    3-Z-[1-(4-((N-(2-methoxy-ethyl)-N-methyl-amino)-methyl)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (273)    3-Z-[1-(4-((N-(2-hydroxy-ethyl)-N-methyl-amino)-methyl)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (274)    3-Z-[1-(4-((N-(dioxolan-2-yl-methyl)-N-methyl-amino)-methyl)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (275)    3-Z-[1-(4-(3-oxo-piperazin-1-yl-methyl)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (276)    3-Z-[l-(4-(N-(piperazin-1-yl-methylcarbonyl)-N-isopropyl-amino)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (277)    3-Z-[1-(4-(N-((2-(piperazin-1-yl)-ethyl)-carbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (278)    3-Z-[1-(4-((N-(3-amino-propyl)-N-methyl-amino)-methyl)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (279)    3-Z-[1-(4-(N-(3-methylamino-propyl)-N-methylsulphonyl-amino)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (280)    3-Z-[1-(4-Ureidomethyl-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (281)    3-Z-[1-(4-guanidinomethyl-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (282)    3-Z-[1-(4-(N-methylsulphonyl-aminomethyl)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (283)    3-Z-[1-(4-(4-benzoyl-piperazin-1-yl-methyl)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (284)    3-Z-[1-(4-((N-(3-acetylamino-propyl)-N-methyl-amino)-methyl)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (285)    3-Z-[1-(4-((N-(3-methylsulphonylamino-propyl)-N-methyl-amino)-methyl)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (286)    3-Z-[1-(4-((N-carboxymethyl-N-methyl-amino)-methyl)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (287)    3-Z-(1-anilino-1-phenyl-methylene)-6-methoxycarbonyl-2-indolinone-   (288)    3-Z-[1-(4-nitro-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (289)    3-Z-[1-(4-fluoro-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (290)    3-Z-[1-(4-chloro-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (291)    3-Z-[1-(4-bromo-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (292)    3-Z-[1-(4-iodo-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (293)    3-Z-[1-(4-cyano-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (294)    3-Z-[1-(4-carboxy-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (295)    3-Z-[1-(4-methoxy-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (296)    3-Z-[1-(4-ethoxy-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (297)    3-Z-[1-(4-trifluoromethyl-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (298)    3-Z-[1-(4-methylmercapto-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (299)    3-Z-[1-(4-(isopropylaminomethyl)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (300)    3-Z-[1-(4-(anilinomethyl)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (301)    3-Z-[1-(4-(isobutylaminomethyl)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (302)    3-Z-[1-(4-(cyclohexylaminomethyl)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (303)    3-Z-[1-(4-(benzylaminomethyl)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (304)    3-Z-[1-(4-((N-methyl-N-propyl-amino)-methyl)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (305)    3-Z-[1-(4-((N-isopropyl-N-methyl-amino)-methyl)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (306)    3-Z-[1-(4-((N-ethyl-N-propyl-amino)-methyl)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (307)    3-Z-[1-(4-((N-ethyl-N-isopropyl-amino)-methyl)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (308)    3-Z-[1-(4-(dipropylaminomethyl)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (309)    3-Z-[1-(4-(diisopropylaminomethyl)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (310)    3-Z-[1-(4-((N-benzyl-N-ethyl-amino)-methyl)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (311)    3-Z-[1-(4-(dibenzylaminomethyl)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (312)    3-Z-[1-(4-(3,6-dihydro-2H-pyridin-1-yl-methyl)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (313)    3-Z-[1-(4-(3,5-dimethyl-piperidin-1-yl-methyl)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (314)    3-Z-[1-(4-(azepan-1-yl-methyl)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (315)    3-Z-[1-(4-(2-amino-ethyl)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (316)    3-Z-[1-(4-(2-methylamino-ethyl)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (317)    3-Z-[1-(4-(2-ethylamino-ethyl)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (318)    3-Z-[1-(4-(2-dimethylamino-ethyl)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (319)    3-Z-[1-(4-(2-diethylamino-ethyl)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (320)    3-Z-[1-(4-(2-piperidin-1-yl-ethyl)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (321)    3-Z-[1-(4-(2-acetylamino-ethyl)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (322)    3-Z-[1-(4-(3-amino-propyl)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (323)    3-Z-[1-(4-(3-dimethylamino-propyl)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (324)    3-Z-[1-(4-(N-aminomethylcarbonyl-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (325)    3-Z-[1-(4-(N-ethylaminomethylcarbonyl-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (326)    3-Z-[1-(4-(N-diethylaminomethylcarbonyl-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (327)    3-Z-[1-(4-(N-dipropylaminomethylcarbonyl-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-indolinone-   (328)    3-Z-[1-(4-(N—((N-ethyl-N-methyl-amino)-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (329)    3-Z-[1-(4-(N—((N-ethyl-N-propyl-amino)-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (330)    3-Z-[1-(4-(N—((N-methyl-N-propyl-amino)-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (331)    3-Z-[1-(4-(N-dimethylaminomethylcarbonyl-N-ethyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (332)    3-Z-[1-(4-(N-dimethylaminomethylcarbonyl-N-propyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-indolinone-   (333)    3-Z-[1-(4-(N-dimethylaminomethylcarbonyl-N-butyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (334)    3-Z-[1-(4-(N-(2-amino-ethylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (335)    3-Z-[1-(4-(N-(2-diethylamino-ethylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-indolinone-   (336)    3-Z-[1-(4-(N-acetyl-N-(2-aminoethyl)-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (337)    3-Z-[1-(4-(N-acetyl-N-(2-methylamino-ethyl)-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (338)    3-Z-[1-(4-(N-acetyl-N-(3-methylamino-propyl)-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (339)    3-Z-[1-(4-(N-acetyl-N-(2-piperidin-1-yl-ethyl)-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (340)    3-Z-[1-(4-(N-acetyl-N-(aminocarbonylmethyl)-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (341)    3-Z-[l-(4-(N-acetyl-N-(piperidin-1-yl-carbonylmethyl)-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-indolinone-   (342)    3-Z-[1-(4-(N-methyl-N-(aminocarbonyl)-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (343)    3-Z-[1-(4-(N-methyl-N-(methylaminocarbonyl)-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (344)    3-Z-[1-(4-(N-methyl-N-(dimethylaminocarbonyl)-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (345)    3-Z-[1-(4-(N-methyl-N-(piperidin-1-yl-carbonyl)-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (346)    3-Z-[1-(4-(N-(2-ethylamino-ethyl)-N-methylsulphonyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (347)    3-Z-[1-(4-(N-(2-diethylamino-ethyl)-N-methylsulphonyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (348)    3-Z-[1-(4-(N-(2-pyrrolidin-1-yl-ethyl)-N-methylsulphonyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (349)    3-Z-[1-(4-(N-(2-piperidin-1-yl-ethyl)-N-methylsulphonyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (350)    3-Z-[1-(4-(N-(2-piperazin-1-yl-ethyl)-N-methylsulphonyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (351)    3-Z-[1-(4-(N-(2-(4-morpholin-1-yl)-ethyl)-N-methylsulphonyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (352)    3-Z-[1-(4-(N-(ethylaminocarbonylmethyl)-N-methylsulphonyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (353)    3-Z-[1-(4-(N-(diethylaminocarbonylmethyl)-N-methylsulphonyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (354)    3-Z-[1-(4-(N-(pyrrolidin-1-yl-carbonylmethyl)-N-methylsulphonyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (355)    3-Z-[1-(4-(N-(piperidin-1-yl-carbonylmethyl)-N-methyl-sulphonyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (356)    3-Z-[1-(4-(N-(piperazin-1-yl-carbonylmethyl)-N-methyl-sulphonyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (357)    3-Z-[1-(4-(N-((morpholin-4-yl)-carbonylmethyl)-N-methylsulphonyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (358)    3-Z-[1-(4-(2-dimethylamino-ethoxy)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (359)    3-Z-[1-(4-(3-dimethylamino-propoxy)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (360)    3-Z-[1-(4-(aminocarbonylmethyl)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (361)    3-Z-[1-(4-(2-aminocarbonyl-ethyl)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (362)    3-Z-[1-(4-(pyridin-2-yl)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (363)    3-Z-[1-(4-(pyridine-3-yl)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (364)    3-Z-[1-(4((N-phenethyl-N-methyl-amino)-methyl)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (365)    3-Z-[1-(4-(N-acetyl-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (366)    3-Z-[1-(4-(N-ethylcarbonyl-N-(dimethylaminocarbonyl-methyl)-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (367)    3-Z-[1-(4-(N-methyl-N-methylsulphonyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (368)    3-Z-[1-(4-carboxymethyl-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (369)    3-Z-[1-(4-carbamoylmethyl-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (370)    3-Z-[1-(4-dimethylcarbamoylmethyl-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (371)    3-Z-[1-(4-tetrazol-5-yl-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (372)    3-Z-[1-(4-(piperidin-1-yl-methyl)-anilino)-methylene]-6-methoxycarbonyl-2-indolinone-   (373)    3-Z-[1-(4-(piperidin-1-yl-methyl)-anilino)-ethylidene]-6-methoxycarbonyl-2-indolinone-   (374)    3-Z-[1-(4-(piperidin-1-yl-methyl)-anilino)-propylidene]-6-methoxycarbonyl-2-indolinone-   (375)    3-Z-[1-(4-(piperidin-1-yl-methyl)-anilino)-butylidene]-6-methoxycarbonyl-2-indolinone-   (376)    3-Z-[1-(4-(N-(3-dimethylamino-propyl)-N-acetyl-amino)-anilino)-methylene]-6-methoxycarbonyl-2-indolinone-   (377)    3-Z-[1-(4-(N-(3-dimethylamino-propyl)-N-acetyl-amino)-anilino)-ethylidene]-6-methoxycarbonyl-2-indolinone-   (378)    3-Z-[1-(4-(N-(3-dimethylamino-propyl)-N-acetyl-amino)-anilino)-propylidene]-6-methoxycarbonyl-2-indolinone-   (379)    3-Z-[1-(4-(N-(3-dimethylamino-propyl)-N-acetyl-amino)-anilino)-butylidene]-6-methoxycarbonyl-2-indolinone-   (380)    3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-methylsulphonyl-amino)-anilino)-methylene]-6-methoxycarbonyl-2-indolinone-   (381)    3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-methylsulphonyl-amino)-anilino)-ethylidene]-6-methoxycarbonyl-2-indolinone-   (382)    3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-methylsulphonyl-amino)-anilino)-propylidene]-6-methoxycarbonyl-2-indolinone-   (383)    3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-methylsulphonyl-amino)-anilino)-butylidene]-6-methoxycarbonyl-2-indolinone-   (384)    3-Z-[1-(4-tetrazol-5-yl-anilino)-methylene]-6-methoxycarbonyl-2-indolinone-   (385)    3-Z-[1-(4-tetrazol-5-yl-anilino)-ethylidene]-6-methoxycarbonyl-2-indolinone-   (386)    3-Z-[1-(4-tetrazol-5-yl-anilino)-propylidene]-6-methoxycarbonyl-2-indolinone-   (387)    3-Z-[1-(4-tetrazol-5-yl-anilino)-butylidene]-6-methoxycarbonyl-2-indolinone-   (388)    3-Z-[1-(4-carboxy-anilino)-methylene]-6-methoxycarbonyl-2-indolinone-   (389)    3-Z-[1-(4-carboxy-anilino)-ethylidene]-6-methoxycarbonyl-2-indolinone-   (390)    3-Z-[1-(4-carboxy-anilino)-propylidene]-6-methoxycarbonyl-2-indolinone-   (391)    3-Z-[1-(4-carboxy-anilino)-butylidene]-6-methoxycarbonyl-2-indolinone-   (392)    3-Z-[1-(4-(N-benzyl-N-methyl-aminomethyl)-anilino)-1-methyl-methylene]-6-methoxycarbonyl-2-indolinone-   (393)    3-Z-[1-(4-(2,3,4,5-tetrahydro-benzo(d)azepin-3-yl-methyl)-anilino)-1-methyl-methylene]-6-methoxycarbonyl    indolinone-   (394)    3-Z-[1-(4-((benzo(1,3)dioxol-5-yl-methyl)-methyl-amino-methyl)-anilino)-1-methyl-methylene]-6-methoxycarbonyl-2-indolinone-   (395)    3-Z-[1-(4-(N-phenethyl-N-methyl-aminomethyl)-anilino)-1-methyl-methylene]-6-methoxycarbonyl-2-indolinone-   (396)    3-Z-[1-(4-(N-(3,4-dimethoxy-benzyl)-N-methyl-amino-methyl)-anilino)-1-methyl-methylene]-6-methoxycarbonyl    indolinone-   (397)    3-Z-[1-(4-(N-(4-chloro-benzyl)-N-methyl-amino-methyl)-anilino)-1-methyl-methylene]-6-methoxycarbonyl-2-indolinone-   (398)    3-Z-[1-(4-(N-(4-methylbenzyl)-N-methyl-amino-methyl)-anilino)-1-methyl-methylene]-6-methoxycarbonyl-2-indolinone-   (399)    3-Z-[1-(4-(N-(4-fluoro-benzyl)-N-methyl-amino-methyl)-anilino)-1-methyl-methylene]-6-methoxycarbonyl-2-indolinone-   (400)    3-Z-[1-(4-(N-(4-bromo-benzyl)-N-methyl-amino-methyl)-anilino)-1-methyl-methylene]-6-methoxycarbonyl-2-indolinone-   (401)    3-Z-[1-(4-(N-(3-dimethylamino-propionyl)-N-dimethylaminocarbonylmethyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (402)    3-Z-[1-(4-(N-(4-dimethylamino-butyryl)-N-dimethylaminocarbonylmethyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (403)    3-Z-[1-(4-(N-dimethylaminocarbonylmethyl-N-(2-dimethylamino-ethylsulphonyl)-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (404)    3-Z-[1-(4-(N-dimethylaminocarbonylmethyl-N-(3-dimethylamino-propylsulphonyl)-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (405)    3-Z-[1-(4-((2-hydroxy-ethyl)-amino-methyl)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (406)    3-Z-[1-(4-((2-methoxy-ethyl)-amino-methyl)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (407)    3-Z-[1-(4-((2-dimethylamino-ethyl)-amino-methyl)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (408)    3-Z-[1-(4-((3-dimethylamino-propyl)-amino-methyl)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (409)    3-Z-[1-(4-((N-tert.butoxycarbonyl-2-amino-ethyl)-amino-methyl)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (410)    3-Z-[1-(4-((N-tert.butoxycarbonyl-3-amino-propyl)-amino-methyl)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (411)    3-Z-[1-(4-((2-amino-ethyl)-amino-methyl)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (412)    3-Z-[1-(4-((3-amino-propyl)-amino-methyl)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (413)    3-Z-[1-(4-((2-acetylamino-ethyl)-amino-methyl)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (414)    3-Z-[1-(4-((3-acetylamino-propyl)-amino-methyl)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (415)    3-Z-[1-(4-((2-methylsulphonylamino-ethyl)-amino-methyl)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl    indolinone-   (416)    3-Z-[1-(4-((3-methylsulphonylamino-propyl)-amino-methyl)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl    indolinone-   (417)    3-Z-[1-(4-(N—(N-tert.butoxycarbonyl-2-amino-ethyl)-N-methyl-amino-methyl)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (418)    3-Z-[1-(4-(N-(2-amino-ethyl)-N-methyl-amino-methyl)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (419)    3-Z-[1-(4-(N-(2-acetylamino-ethyl)-N-methyl-amino-methyl)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl    indolinone-   (420)    3-Z-[1-(4-(N-(2-methylsulphonylamino-ethyl)-N-methyl-amino-methyl)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (421)    3-Z-[1-(4-(carboxymethyl-amino-methyl)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (422)    3-Z-[1-(4-(ethoxycarbonylmethyl-amino-methyl)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (423)    3-Z-[1-(4-(carbamoylmethyl-amino-methyl)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (424)    3-Z-[1-(4-(dimethylcarbamoyl-methyl-amino-methyl)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (425)    3-Z-[1-(4-(methylcarbamoyl-methyl-amino-methyl)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (426)    3-Z-[1-(4-(N-dimethylaminomethylcarbonyl-N-methyl-amino)-3-amino-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (427)    3-Z-[1-(4-(N-dimethylaminomethylcarbonyl-N-methyl-amino)-3-nitro-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (428)    3-Z-[1-(4-(N-dimethylaminomethylcarbonyl-N-methyl-amino)-3-acetylamino-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (429)    3-Z-[1-(4-(N-dimethylaminomethylcarbonyl-N-methyl-amino)-3-methylsulphonylamino-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (430)    3-Z-[1-(4-(N-dimethylaminomethylcarbonyl-N-methyl-amino)-3-cyano-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (431)    3-Z-[1-(4-(N-dimethylaminomethylcarbonyl-N-methyl-amino)-3-hydroxy-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (432)    3-Z-[1-(4-(N-dimethylaminomethylcarbonyl-N-methyl-amino)-3-methoxy-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (433)    3-Z-[1-(4-(N-dimethylaminomethylcarbonyl-N-methyl-amino)-3-ethoxycarbonyl-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (434)    3-Z-[1-(4-(N-dimethylaminomethylcarbonyl-N-methyl-amino)-3-carboxy-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (435)    3-Z-[1-(4-(N-dimethylaminomethylcarbonyl-N-methyl-amino)-3-carbamoyl-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (436)    3-Z-[1-(4-(N-dimethylaminomethylcarbonyl-N-methyl-amino)-3-chloro-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (437)    3-Z-[1-(4-(N-dimethylaminomethylcarbonyl-N-methyl-amino)-3-fluoro-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (438)    3-Z-[1-(4-(N-dimethylaminomethylcarbonyl-N-methyl-amino)-3-bromo-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (439)    3-Z-[1-(4-(N-dimethylaminomethylcarbonyl-N-methyl-amino)-3-methyl-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (440)    3-Z-[1-(4-(N-dimethylaminomethylcarbonyl-N-methyl-amino)-3-trifluoromethyl-anilino)-1-phenyl-methylene]-methoxycarbonyl-2-indolinone-   (441)    3-Z-[1-(4-(N-dimethylaminomethylcarbonyl-N-methyl-amino)-3,5-dibromo-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (442)    3-Z-[1-(4-(N-dimethylaminomethylcarbonyl-N-methyl-amino)-3,5-dichloro-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (443)    3-Z-[1-(4-(dimethylaminomethyl)-3-amino-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (444)    3-Z-[1-(4-(dimethylaminomethyl)-3-nitro-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (445)    3-Z-[1-(4-(dimethylaminomethyl)-3-acetylamino-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (446)    3-Z-[1-(4-(dimethylaminomethyl)-3-methylsulphonylamino-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (447)    3-Z-[1-(4-(dimethylaminomethyl)-3-cyano-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (448)    3-Z-[1-(4-(dimethylaminomethyl)-3-hydroxy-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (449)    3-Z-[1-(4-(dimethylaminomethyl)-3-methoxy-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (450)    3-Z-[1-(4-(dimethylaminomethyl)-3-ethoxycarbonyl-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (451)    3-Z-[1-(4-(dimethylaminomethyl)-3-carboxy-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (452)    3-Z-[1-(4-(dimethylaminomethyl)-3-carbamoyl-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (453)    3-Z-[1-(4-(dimethylaminomethyl)-3-chloro-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (454)    3-Z-[1-(4-(dimethylaminomethyl)-3-fluoro-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (455)    3-Z-[1-(4-(dimethylaminomethyl)-3-bromo-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (456)    3-Z-[1-(4-(dimethylaminomethyl)-3-methyl-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (457)    3-Z-[1-(4-(dimethylaminomethyl)-3-trifluoromethyl-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (458)    3-Z-[1-(4-dimethylaminomethyl-3,5-dibromo-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (459)    3-Z-[1-(4-(dimethylaminomethyl)-3,5-dichloro-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (460)    3-Z-[1-(4-(dimethylaminomethyl)-anilino)-1-phenyl-methylene]-6-[(2-hydroxy-ethoxy)-carbonyl]-2-indolinon-   (461)    3-Z-[1-(4-(dimethylaminomethyl)-anilino)-1-phenyl-methylene]-6-[(ethoxycarbonyl-methoxy)-carbonyl]-2-indolinone-   (462)    3-Z-[1-(4-(dimethylaminomethyl)-anilino)-1-phenyl-methylene]-6-[(carboxy-methoxy)-carbonyl]-2-indolinone-   (463)    3-Z-[1-(4-(dimethylaminomethyl)-anilino)-1-phenyl-methylene]-6-[(carbamoyl-methoxy)-carbonyl]-2-indolino-   (464)    3-Z-[1-(4-(N-dimethylaminomethylcarbonyl-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-[(2-hydroxy-ethoxy)    carbonyl]-2-indolinone-   (465)    3-Z-[1-(4-(N-dimethylaminomethylcarbonyl-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-[(ethoxycarbonyl-methoxy)-carbonyl]-2-indolinone-   (466)    3-Z-[1-(4-(N-dimethylaminomethylcarbonyl-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-[(carboxy-methoxy)    carbonyl]-2-indolinone-   (467)    3-Z-[1-(4-(N-dimethylaminomethylcarbonyl-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-[(carbamoyl-methoxy)-carbonyl]-2-indolinone-   (468)    3-Z-[1-(4-(N-dimethylaminomethylcarbonyl-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-[(2-methoxy-ethoxy)-carbonyl]-2-indolinone-   (469)    3-Z-[1-(4-(N-dimethylaminomethylcarbonyl-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-[(2-dimethylamino-ethoxy)-carbonyl]-2-indolinone-   (470)    3-Z-[1-(4-(N-dimethylaminomethylcarbonyl-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-[(2-(N-tert.butoxycarbonyl-amino)-ethoxy)-carbonyl]-2-indolinone-   (471)    3-Z-[1-(4-(N-dimethylaminomethylcarbonyl-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-[(2-amino-ethoxy)    carbonyl]-2-indolinone-   (472)    3-Z-[1-(4-(N-dimethylaminomethylcarbonyl-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-[(2,2,2-trifluoroethoxy)-carbonyl]-2-indolinone-   (473)    3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (474)    3-Z-[1-(4-(N-(imidazo-1-yl-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (475) 3-Z-[1-(4-(N-(phthalimido-2-yl-methylcarbonyl)-N    methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (476)    3-Z-[1-(4-(N-aminomethylcarbonyl-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (477)    3-Z-[1-(4-(N-acetylaminomethylcarbonyl-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-indolinone-   (478)    3-Z-[1-(4-(N-methylsulphonylaminomethylcarbonyl-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (479)    3-Z-[1-(4-(N—((N-(2-methoxyethyl)-N-methyl-amino)-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (480)    3-Z-[1-(4-(N—((N-(2-dimethylaminoethyl)-N-methyl-amino)-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (481)    3-Z-[1-(4-(N-((di-(2-hydroxyethyl)-amino)-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (482)    3-Z-[1-(4-tert.butoxycarbonylmethyl-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (483)    3-Z-[1-(4-(N-dimethylaminomethylcarbonyl-N-methyl-amino)-anilino)-methylene]-6-methoxycarbonyl-2-indolinone-   (484)    3-Z-[1-(4-(N-dimethylaminomethylcarbonyl-N-methyl-amino)-anilino)-ethylidene]-6-methoxycarbonyl-2-indolinone-   (485)    3-Z-[1-(4-(N-dimethylaminomethylcarbonyl-N-methyl-amino)-anilino)-propylidene]-6-methoxycarbonyl-2-indolinone-   (486)    3-Z-[1-(4-(N-dimethylaminomethylcarbonyl-N-methyl-amino)-anilino)-butylidene]-6-methoxycarbonyl-2-indolinone-   (487)    3-Z-[1-(4-(dimethylaminomethyl)-anilino)-methylene]-6-methoxycarbonyl-2-indolinone-   (488)    3-Z-[1-(4-(dimethylaminomethyl)-anilino)-ethylidene]-6-methoxycarbonyl-2-indolinone-   (489)    3-Z-[1-(4-(dimethylaminomethyl)-anilino)-propylidene]-6-methoxycarbonyl-2-indolinone-   (490)    3-Z-[1-(4-(dimethylaminomethyl)-anilino)-butylidene]-6-methoxycarbonyl-2-indolinone-   (491)    3-Z-[1-(4-tert.butyloxycarbonyl-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (492)    3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (493)    3-Z-[1-(4-(N-(3-dimethylamino-propyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (494)    3-Z-[1-(4-(N-methyl-acetylamino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (495)    3-Z-[1-(4-(imidazol-4-yl)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (496)    3-Z-[1-(4-((N-(dioxolan-2-yl-methyl)-N-methyl-amino)-methyl)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl    2-indolinone-   (497)    3-Z-[1-(4-(N-benzyl-N-methyl-amino-methyl)-anilino)-1-methyl-methylene]-6-carbamoyl-2-indolinone-   (498)    3-Z-[1-(4-(2,3,4,5-tetrahydro-benzo(d)azepin-3-yl-methyl)-anilino)-1-methyl-methylene]-6-carbamoyl-2-indolinone-   (499)    3-Z-[1-(4-((benzo(1,3)dioxol-5-yl-methyl)-methyl-amino-methyl)-anilino)-1-methyl-methylene]-6-carbamoyl-2-indolinone-   (500)    3-Z-[1-(4-(N-phenethyl-N-methyl-amino-methyl)-anilino)-1-methyl-methylene]-6-carbamoyl-2-indolinone-   (501)    3-Z-[1-(4-(N-(3,4-dimethoxy-benzyl)-N-methyl-amino-methyl)-anilino)-1-methyl-methylene]-6-carbamoyl-2-indolinone-   (502)    3-Z-[1-(4-(N-(4-chloro-benzyl)-N-methyl-amino-methyl)-anilino)-1-methyl-methylene]-6-carbamoyl-2-indolinone-   (503)    3-Z-[1-(4-(N-(4-methyl-benzyl)-N-methyl-amino-methyl)-anilino)-1-methyl-methylene]-6-carbamoyl-2-indolinone-   (504)    3-Z-[1-(4-(N-(4-fluoro-benzyl)-N-methyl-amino-methyl)-anilino)-1-methyl-methylene]-6-carbamoyl-2-indolinone-   (505)    3-Z-[1-(4-(N-(4-bromo-benzyl)-N-methyl-amino-methyl)-anilino)-1-methyl-methylene]-6-carbamoyl-2-indolinone-   (506)    3-Z-[1-(4-((N-(2-methoxy-ethyl)-N-methyl-amino)-methyl)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (507)    3-Z-[1-(4-(dimethylaminomethyl)-anilino)-1-phenyl-methylene]-6-[(2-amino-ethoxy)-carbonyl]-2-indolinone-   (508)    3-Z-[1-(4-((N-(3-methylsulfonylamino-propyl)-N-methyl-amino)-methyl)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (509)    3-Z-[1-(4-(piperidin-1-yl-methyl)-anilino)-1-phenyl-methylene]-6-carbamoyl-2-indolinone-trifluoroacetate-   (510) 3-Z-(1-anilino-1-phenyl-methylene)-6-carbamoyl-2-indolinone-   (511)    3-Z-[1-(4-dimethylaminomethyl-anilino)-1-phenyl-methylene]-6-carbamoyl-2-indolinone-trifluoroacetate-   (512)    3-Z-[1-(4-(2-diethylamino-ethyl)-anilino)-1-phenyl-methylene]-6-carbamoyl-2-indolinone-trifluoroacetate-   (513)    3-Z-[1-(4-(morpholin-4-yl-methyl)-anilino)-1-phenyl-methylene]-6-carbamoyl-2-indolinone-trifluoroacetate-   (514)    3-Z-[1-(4-(1-oxo-thiomorpholin-4-yl-methyl)-anilino)-1-phenyl-methylene]-6-carbamoyl-2-indolinone-trifluoroacetate-   (515)    3-Z-[1-(4-(1,1-dioxo-thiomorpholin-4-yl-methyl)-anilino)-1-phenyl-methylene]-6-carbamoyl-2-indolinone-trifluoroacetate (516)    3-Z-[1-(4-(benzylaminomethyl)-anilino)-1-phenyl-methylene]-6-carbamoyl-2-indolinone-trifluoroacetate-   (517)    3-Z-[1-(4-(amino-methyl)-anilino)-1-phenyl-methylene]-6-carbamoyl-2-indolinone-trifluoroacetate-   (518)    3-Z-[1-(4-(2,6-dimethylpiperidin-1-yl-methyl)-anilino)-1-phenyl-methylene]-6-carbamoyl-2-indolinone-trifluoroacetate-   (519)    3-Z-[1-(4-(pyrrolidin-1-yl-methyl)-anilino)-1-phenyl-methylene]-6-carbamoyl-2-indolinone-trifluoroacetate-   (520)    3-Z-[1-(3-(dimethylaminomethyl)-anilino)-1-phenyl-methylene]-6-carbamoyl-2-indolinone-trifluoroacetate-   (521)    3-Z-[1-(3-(N-methyl-N-ethyl-aminomethyl)-anilino)-1-phenyl-methylene]-6-carbamoyl-2-indolinone-trifluoroacetate-   (522)    3-Z-[1-(3-(methylaminomethyl)-anilino)-1-phenyl-methylene]-6-carbamoyl-2-indolinone-trifluoroacetate-   (523)    3-Z-[1-(3-hydroxymethyl-anilino)-1-phenyl-methylene]-6-carbamoyl-2-indolinone-   (524)    3-Z-[1-(4-(methoxycarbonylmethyl-aminomethyl)-anilino)-1-phenyl-methylene]-6-carbamoyl-2-indolinone-trifluoroacetate-   (525)    3-Z-[1-(4-(N-methylsulphonyl-N-(dimethylaminocarbonyl-methyl)-amino)-anilino)-1-phenyl-methylene]-6-carbamoyl    2-indolinone-   (526)    3-Z-[1-(4-(N-acetyl-aminomethyl)-anilino)-1-phenyl-methylene]-6-carbamoyl-2-indolinone-   (527)    3-Z-[1-(3,4-dimethoxy-anilino)-1-phenyl-methylene]-6-carbamoyl-2-indolinone-   (528)    3-Z-[1-(4-(morpholin-4-yl)-anilino)-1-phenyl-methylene]-6-carbamoyl-2-indolinone-trifluoroacetate-   (529)    3-Z-[1-(4-acetylamino-anilino)-1-phenyl-methylene]-6-carbamoyl-2-indolinone-   (530)    3-Z-[1-(4-amino-anilino)-1-phenyl-methylene]-6-carbamoyl-2-indolinone-   (531)    3-Z-[1-(4-N-methyl-N-acetyl-amino-anilino)-1-phenyl-methylene]-6-carbamoyl-2-indolinone-   (532)    3-Z-[1-(4-ethoxycarbonyl-anilino)-1-phenyl-methylene]-6-carbamoyl-2-indolinone-   (533)    3-Z-[1-(4-carboxy-anilino)-1-phenyl-methylene]-6-carbamoyl-2-indolinone-   (534)    3-Z-[1-(4-benzylcarbamoyl-anilino)-1-phenyl-methylene]-6-carbamoyl-2-indolinone-   (535)    3-Z-[1-(cyclohexyl-amino)-1-phenyl-methylene]-6-carbamoyl-2-indolinone-   (536)    3-Z-[1-(4-amino-cyclohexyl-amino)-1-phenyl-methylene]-6-carbamoyl-2-indolinone-trifluoroacetate-   (537)    3-Z-[1-(N-methyl-piperidine-4-yl-amino)-1-phenyl-methylene]-6-carbamoyl-2-indolinone-trifluoroacetate-   (538)    3-Z-[1-(4-(piperidin-1-yl-methyl)-anilino)-1-methyl-methylene]-6-carbamoyl-2-indolinone-trifluoroacetate-   (539)    3-Z-[1-(3-dimethylaminomethyl-anilino)-1-methyl-methylene]-6-carbamoyl-2-indolinone-trifluoroacetate-   (540)    3-Z-[1-(4-(N-methyl-N-benzyl-aminomethyl)-anilino)-1-methyl-methylene]-6-carbamoyl-2-indolinone-trifluoroacetate-   (541)    3-Z-[1-(4-(N-methylsulphonyl-N-(2-dimethylamino-ethyl)-amino)-anilino)-1-methyl-methylene]-6-carbamoyl-2-indolinone-trifluoroacetate-   (542)    3-Z-[1-(4-chloro-anilino)-1-methyl-methylene]-6-carbamoyl-2-indolinone-   (543)    3-Z-[1-(3-chloro-anilino)-1-methyl-methylene]-6-carbamoyl-2-indolinone-   (544)    3-Z-[1-(4-methoxycarbonyl-anilino)-1-methyl-methylene]-6-carbamoyl-2-indolinone-   (545)    3-Z-[1-(4-carboxy-anilino)-1-methyl-methylene]-6-carbamoyl-2-indolinone-   (546)    3-Z-[1-(4-methyl-3-nitro-anilino)-1-methyl-methylene]-6-carbamoyl-2-indolinone-   (547)    3-Z-[1-(4-(piperidin-1-yl-methyl)-anilino)-1-propyl-methylene]-6-carbamoyl-2-indolinone-trifluoroacetate-   (548)    3-Z-[1-(3-dimethylaminomethyl-anilino)-1-propyl-methylene]-6-carbamoyl-2-indolinone-trifluoroacetate-   (549)    3-Z-[1-(4-(N-methyl-N-benzyl-aminomethyl)-anilino)-1-propyl-methylene]-6-carbamoyl-2-indolinone-trifluoroacetate-   (550)    3-Z-[1-(4-(N-methylsulphonyl-N-(2-dimethylamino-ethyl)-amino)-anilino)-1-propyl-methylene]-6-carbamoyl-2-indolinone-trifluoroacetate-   (551)    3-Z-[1-(4-chloro-anilino)-1-propyl-methylene]-6-carbamoyl-2-indolinone-   (552)    3-Z-[1-(3-chloro-anilino)-1-propyl-methylene]-6-carbamoyl-2-indolinone-   (553)    3-Z-[1-(4-methoxycarbonyl-anilino)-1-propyl-methylene]-6-carbamoyl-2-indolinone-   (554)    3-Z-[1-(4-carboxy-anilino)-1-propyl-methylene]-6-carbamoyl-2-indolinone-   (555)    3-Z-[1-(4-methyl-3-nitro-anilino)-1-propyl-methylene]-6-carbamoyl-2-indolinone-   (556)    3-Z-[1-(3-(piperidin-1-yl-methyl)-anilino)-1-phenyl-methylene]-6-carbamoyl-2-indolinone-trifluoroacetate-   (557)    3-Z-[1-(3-(diethylaminomethyl)-anilino)-1-phenyl-methylene]-6-carbamoyl-2-indolinone-trifluoroacetate-   (558)    3-Z-[1-(3-(benzylaminomethyl)-anilino)-1-phenyl-methylene]-6-carbamoyl-2-indolinone-trifluoroacetate-   (559)    3-Z-[1-(3-(N-methyl-N-benzyl-aminomethyl)-anilino)-1-phenyl-methylene]-6-carbamoyl-2-indolinone-trifluoroacetate-   (560)    3-Z-[1-(3-(butylaminomethyl)-anilino)-1-phenyl-methylene]-6-carbamoyl-2-indolinone-trifluoroacetate-   (561)    3-Z-[1-(3-(aminomethyl)-anilino)-1-phenyl-methylene]-6-carbamoyl-2-indolinone-trifluoroacetate-   (562)    3-Z-[1-(3-(N-(3-dimethylaminopropyl)-N-methyl-amino-methyl)-anilino)-1-phenyl-methylene]-6-carbamoyl-2-indolinone-trifluoroacetate-   (563)    3-Z-[1-(3-(N-(2-dimethylaminoethyl)-N-methyl-aminomethyl)-anilino)-1-phenyl-methylene]-6-carbamoyl-indolinone-trifluoroacetate-   (564)    3-Z-[1-(4-(piperidin-1-yl-methyl)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (565)    3-Z-[1-(4-bromo-anilino)-1-phenyl-methylene]-6-ethoxy-carbonyl-2-indolinone-   (566)    3-Z-[1-(3-(dimethylaminomethyl)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (567)    3-Z-[1-(4-(dimethylaminomethyl)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (568)    3-Z-[1-(4-[(2,6-dimethyl-piperidin-1-yl)-methyl]-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (569)    3-Z-[1-(4-(2-dimethylamino-ethyl)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (570)    3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-acetyl-amino)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (571)    3-Z-[1-(4-tert.butyloxycarbonyl-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (572)    3-Z-[1-(4-(N-(3-dimethylamino-propyl)-N-acetyl-amino)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (573)    3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-methylsulponyl-amino)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (574)    3-Z-[1-(4-(4-methyl-piperazin-1-yl)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (575)    3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (576)    3-Z-[1-(4-(N-(3-dimethylamino-propyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (577)    3-Z-[1-(4-(N-methyl-acetylamino)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (578)    3-Z-[1-(4-(N-methyl-methylsulphonylamino)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (579)    3-Z-[1-(4-(N-(3-dimethylamino-propyl)-N-methylsulphonyl-amino)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (580)    3-Z-[1-(4-(N-dimethylaminocarbonylmethyl-N-methylsulphonyl-amino)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (581)    3-Z-[1-(4-(imidazol-4-yl)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (582)    3-Z-[1-(4-(tetrazol-5-yl)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (583)    3-Z-[1-(4-(N-benzyl-N-methyl-aminomethyl)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (584)    3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-propionyl-amino)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (585)    3-Z-[1-(4-(pyrrolidin-1-yl-methyl)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (586)    3-Z-[1-(4-(N-methyl-N-phenethyl-aminomethyl)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (587)    3-Z-[1-(4-(N-dimethylaminomethylcarbonyl-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (588)    3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-ethylsulphonyl-amino)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (589)    3-Z-[1-(4-(N-tert.butoxycarbonyl-N-ethyl-aminomethyl-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (590)    3-Z-[1-(4-(piperidin-1-yl-methyl)-anilino)-1-ethyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (591)    3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-methylsulphonyl-amino)-anilino)-1-ethyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (592)    3-Z-[1-(4-(dimethylaminomethyl)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (593)    3-Z-[1-(4-[(2,6-dimethyl-piperidin-1-yl)-methyl]-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (594)    3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-methylsulphonyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (595)    3-Z-[1-(4-(N-(3-dimethylamino-propyl)-N-methylsulphonyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (596)    3-Z-[1-(4-(N-dimethylaminocarbonylmethyl-N-methylsulphonyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (597)    3-Z-[1-(4-(N-acetyl-N-dimethylaminocarbonylmethyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (598)    3-Z-[1-(4-(N-dimethylaminocarbonylmethyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (599)    3-Z-[1-(4-(N-(3-dimethylamino-propyl)-N-acetyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (600)    3-Z-[1-(4-(N-methylaminocarbonylmethyl-N-methylsulphonyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (601)    3-Z-[1-(4-((imidazolidin-2,4-dion-5-ylidene)-methyl)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (602) 3-Z-[1-(4-(N-((2-dimethylamino-ethyl)-carbonyl)-N    methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (603)    3-Z-[1-(4-(N-tert.butoxycarbonyl-aminomethyl)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (604)    3-Z-[1-(4-(2-oxo-pyrrolidin-1-yl-methyl)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (605)    3-Z-[1-(4-(N-aminocarbonylmethyl-N-methylsulphonyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (606)    3-Z-[1-(4-(thiomorpholin-4-yl-methyl)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (607)    3-Z-[1-(4-(1,1-dioxo-thiomorpholin-4-yl-methyl)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (608)    3-Z-[1-(4-(N-cyanomethyl-N-methylsulphonyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (609)    3-Z-[1-(4-(N-tert.butoxycarbonyl-ethylaminomethyl)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (610)    3-Z-[1-(4-(N-benzyl-N-methyl-aminomethyl)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (611)    3-Z-[1-(4-(1-oxo-thiomorpholin-4-yl-methyl)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (612)    3-Z-[1-(4-(2-(imidazol-4-yl)-ethyl)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (613)    3-Z-[1-(4-(morpholin-4-yl-methyl)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (614)    3-Z-[1-(4-((4-methyl-piperazin-1-yl)-methyl)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (615)    3-Z-[1-(4-((2-(N-benzyl-N-methyl-amino)-ethyl)-N-methylsulphonyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (616)    3-Z-[1-(4-cyclohexylamino-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (617)    3-Z-[1-(4-(pyridin-4-yl-methyl)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (618)    3-Z-[1-(4-(imidazol-1-yl-methyl)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (619)    3-Z-[1-(4-(imidazol-1-yl-methyl)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (620)    3-Z-[1-(N-methyl-piperidine-4-yl-amino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (621)    3-Z-[1-(4-(imidazol-4-yl-methyl)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (622)    3-Z-[1-(4-((4-hydroxy-piperidin-1-yl)-methyl)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (623)    3-Z-[1-(4-((4-methoxy-piperidin-1-yl)-methyl)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (624)    3-Z-[1-(4-benzyl-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (625)    3-Z-[1-(4-(N-(3-trifluoroacetylamino-propyl)-N-methylsulphonyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (626)    3-Z-[1-(4-tert.butoxycarbonylmethyl-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (627)    3-Z-[1-(4-tert.butoxycarbonyl-anilino)-1-ethyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (628)    3-Z-[1-(4-(4-tert.butoxycarbonyl-piperazin-1-yl-methyl)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-indolinone-   (629)    3-Z-[1-(4-(1-methyl-imidazol-2-yl)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (630)    3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-methylsulponyl-amino)-3-nitro-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (631)    3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-methylsulphonyl-amino)-3-amino-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (632)    3-Z-[1-(4-((3-(N-benzyl-N-methyl-amino)-propyl)-N-methylsulphonyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (633)    3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-methylsulphonyl-amino)-3-chloro-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (634)    3-Z-[1-(4-(N-dimethylaminomethylcarbonyl-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (635)    3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-acetyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (636)    3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-propionyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (637)    3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-butyryl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (638)    3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-isobutyryl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (639)    3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-benzoyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (640)    3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-acetyl-amino)-3-amino-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (641)    3-Z-[1-(4-(4-hydroxymethyl-piperidin-1-yl-methyl)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (642)    3-Z-[1-(4-(2-(4-hydroxy-piperidin-1-yl)-ethyl)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (643)    3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-propylsulphonyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (644)    3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-butylsulphonyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (645)    3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-phenylsulphonyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (646)    3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-benzylsulphonyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (647)    3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-ethylsulphonyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (648)    3-Z-[1-(4-((imidazolidin-2,4-dion-5-yl)-methyl)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (649)    3-Z-[1-(4-((3-hydroxy-pyrrolidin-1-yl)-methyl)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (650)    3-Z-[1-(4-(cyclohexylyl-methyl)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (651)    3-Z-[1-(4-(cyclohexyl-carbonyl)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (652)    3-Z-[1-(4-diethylaminomethyl-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (653)    3-Z-[1-(4-(N-(n-hexyl)-N-methyl-aminomethyl)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (654)    3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-(furan-2-carbonyl)-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (655)    3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-(2-methoxy-benzoyl)-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (656)    3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-(pyridine-3-carbonyl)-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (657)    3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-(phenyl-acetyl)-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (658)    3-Z-[1-(4-(N-ethyl-N-methyl-aminomethyl)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (659)    3-Z-[1-(4-(imidazol-2-yl)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (660)    3-Z-[1-(4-(1-ethyl-imidazol-2-yl)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (661)    3-Z-[1-(4-(1-benzyl-imidazol-2-yl)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (662)    3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-isopropylsulphonyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (663)    3-Z-[1-(4-(N-(piperidin-1-yl-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (664)    3-Z-[1-(4-(N-(morpholin-4-yl-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (665)    3-Z-[1-(4-(N-((4-benzyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (666)    3-Z-[1-(4-(N-(pyrrolidin-1-yl-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (667)    3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-acetyl-amino)-3-bromo-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (668)    3-Z-[1-(4-(5-methyl-imidazol-4-yl)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (669)    3-Z-[1-(4-(N-((2-dimethylamino-ethyl)-carbonyl)-N-isopropyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (670)    3-Z-[1-(4-(N-((2-dimethylamino-ethyl)-carbonyl)-N-benzyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (671)    3-Z-[1-(4-(N-butyl-N-tert.butoxycarbonyl-aminomethyl)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (672)    3-Z-[1-(4-(N—((N-aminocarbonylmethyl-N-methyl-amino)-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (673)    3-Z-[1-(4-(N—((N-benzyl-N-methyl-amino)-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (674)    3-Z-[1-(4-(N-(di-(2-methoxyethyl)-amino-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (675)    3-Z-[1-(4-(N-((2-(4-tert.butoxycarbonyl-piperazin-1-yl)-ethyl)-carbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (676)    3-Z-[1-(4-(N-((2-(piperidin-1-yl)-ethyl)-carbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (677)    3-Z-[1-(4-(N-((2-(N-benzyl-N-methyl-amino)-ethyl)-carbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (678)    3-Z-[1-(4-(N-dimethylaminomethylcarbonyl-N-isopropyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-indolinone-   (679)    3-Z-[1-(4-(N-(piperidin-1-yl-methylcarbonyl)-N-isopropyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (680)    3-Z-[1-(4-(N-((4-tert.butoxycarbonyl-piperazin-1-yl)-methylcarbonyl)-N-isopropyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (681)    3-Z-[1-(4-(N—((N-benzyl-N-methyl-amino)-methylcarbonyl)-N-benzyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (682)    3-Z-[1-(4-(N-dimethylaminomethylcarbonyl-N-benzyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (683)    3-Z-[1-(4-(N-(piperidin-1-yl-methylcarbonyl)-N-benzyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (684)    3-Z-[1-(4-(1,2,4-triazol-2-yl-methyl)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (685)    3-Z-[1-(4-(1,2,3-triazol-2-yl-methyl)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (686)    3-Z-[1-(4-(1,2,3-triazol-1-yl-methyl)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (687)    3-Z-[1-(4-((N-aminocarbonylmethyl-N-methyl-amino)-methyl)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-   (688)    3-Z-[1-(4-((di-(2-methoxy-ethyl)-amino)-methyl)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (689)    3-Z-[1-(4-(pyrrolidin-1-yl-methyl)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (690)    3-Z-[1-(4-((di-(2-hydroxy-ethyl)-amino)-methyl)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (691)    3-Z-[1-(4-((N-ethoxycarbonylmethyl-N-methyl-amino)-methyl)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-indolinone-   (692)    3-Z-[1-(4-(azetidin-1-yl-methyl)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (693)    3-Z-[1-(4-(N-propyl-N-tert.butoxycarbonyl-aminomethyl)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (694)    3-Z-[1-(4((N-(2-(2-methoxy-ethoxy)-ethyl)-N-methyl-amino)-methyl)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (695)    3-Z-[1-(4-((N-(tert.butoxycarbonyl-3-amino-propyl)-N-methyl-amino)-methyl)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (696)    3-Z-[1-(4-((N-(methylcarbamoyl-methyl)-N-methyl-amino)-methyl)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (697)    3-Z-[1-(4-((N-(dimethylcarbamoyl-methyl)-N-methyl-amino)-methyl)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (698)    3-Z-[1-(4-methyl-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (699)    3-Z-[1-(4-((N-propyl-N-methyl-amino)-methyl)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (700)    3-Z-[1-(4-((N-(2-hydroxy-ethyl)-N-methyl-amino)-methyl)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (701)    3-Z-[1-(4-((N-(2-dimethylamino-ethyl)-N-methyl-amino)-methyl)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (702)    3-Z-[1-(4-((N-(3-dimethylamino-propyl)-N-methyl-amino)-methyl)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (703)    3-Z-[1-(4-(3-oxo-piperazin-1-yl-methyl)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (704)    3-Z-[1-(4-carboxy-anilino)-1-phenyl-methylene]-6-ethoxy-carbonyl-2-indolinone-   (705)    3-Z-[1-(4-aminomethyl-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (706)    3-Z-[1-(4-ethylaminomethyl-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (707)    3-Z-[1-(4-carboxymethyl-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (708)    3-Z-[1-(4-carboxy-anilino)-1-ethyl-methylene]-6-ethoxy-carbonyl-2-indolinone-   (709)    3-Z-[1-(4-(piperazin-1-yl-methyl)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (710)    3-Z-[1-(4-butylaminomethyl-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (711)    3-Z-[1-(4-ethylaminomethyl-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone-   (712)    3-Z-[1-(4-ethylaminomethyl-anilino)-1-phenyl-methylene]-6-carbamoyl-2-indolinone-   (713)    3-Z-[1-(4-(N-(piperazin-1-yl-methylcarbonyl)-N-isopropyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (714)    3-Z-[1-(4-(N-((2-(piperazin-1-yl)-ethyl)-carbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (715)    3-Z-[1-(4-(N-propyl-aminomethyl)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (716)    3-Z-[1-(4-((N-(3-amino-propyl)-N-methyl-amino)-methyl)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (717)    3-Z-[1-(4-(2-dimethylamino-ethoxy)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (718)    3-Z-[1-(3-cyano-4-(N-dimethylaminomethylcarbonyl-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (719)    3-Z-[1-(3-methoxy-4-(N-dimethylaminomethylcarbonyl-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (720)    3-Z-[1-(4-(N-aminomethylcarbonyl-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (721)    3-Z-[1-(4-(N—(N-(2-dimethylamino-ethyl)-N-methyl-aminomethylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (722)    3-Z-[1-(4-(N-(di-(2-hydroxy-ethyl)-amino-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (723)    3-Z-[1-(4-(N-(imidazol-1-yl-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (724)    3-Z-[1-(4-(N-dimethylaminomethylcarbonyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (725)    3-Z-[1-(4-(N-((4-methyl-[1,4]diazepan-1-yl)-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (726)    3-Z-[1-(4-(N-((1-methyl-piperidin-4-yl)-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (727)    3-Z-[1-(2,3-dimethyl-4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (728)    3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (729)    3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-carbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (730)    3-Z-[1-(4-(N-(3-dimethylamino-propyl)-N-acetyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (731)    3-Z-[1-(4-(N-((3-dimethylamino-propyl)-aminocarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (732)    3-Z-[1-anilino-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (733)    3-Z-[1-(4-(N-methyl-N-methylsulphonyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (734)    3-Z-[1-cyclohexylamino-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-   (735)    3-Z-[1-(4-(4-methylpiperazin-1-yl-methyl)-anilino)-1-phenyl-methylene]-6-carboxy-2-indolinone-   (736)    3-Z-[1-(4-methylaminomethyl-anilino)-1-phenyl-methylene]-6-carboxy-2-indolinone-   (737)    3-Z-[1-(4-(morpholin-4-yl-methyl)-anilino)-1-phenyl-methylene]-6-carboxy-2-indolinone-   (738)    3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-methylsulphonyl-amino)-anilino)-1-phenyl-methylene]-6-carboxy-2-indolinone-   (739)    3-Z-[1-(4-(di-(2-hydroxy-ethyl)-amino-methyl)-anilino)-1-phenyl-methylene]-6-carboxy-2-indolinone-   (740)    3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-carboxy-2-indolinone-   (741)    3-Z-[1-(4-(N-(morpholin-4-yl-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-carboxy-2-indolinone-   (742)    3-Z-[1-(4-(N—(N-(2-dimethylamino-ethyl)-N-methyl-aminomethylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-carboxy-2-indolinone-   (743)    3-Z-[1-(4-(2-dimethylamino-ethoxy)-anilino)-1-phenyl-methylene]-6-carboxy-2-indolinone-   (744)    3-Z-[1-cyclohexylamino-1-phenyl-methylene]-6-carboxy-2-indolinone-   (745)    3-Z-[1-(4-dimethylaminomethyl-anilino)-1-(3-(2-carboxy-ethyl)-phenyl)-methylene]-6-methoxycarbonyl-2-indolinone-   (746)    3-Z-[1-(4-(2-dimethylamino-ethyl)-anilino)-1-(3-(2-carboxy-ethyl)-phenyl)-methylene]-6-methoxycarbonyl-2-indolinone-   (747)    3-Z-[1-(4-(1-methyl-imidazol-2-yl)-anilino)-1-(3-(2-carboxy-ethyl)-phenyl)-methylene]-6-methoxycarbonyl-2-indolinone-   (748)    3-Z-[1-(4-dimethylaminomethyl-anilino)-1-(4-(2-carboxy-ethyl)-phenyl)-methylene]-6-methoxycarbonyl-2-indolinone-   (749)    3-Z-[1-(4-(2-dimethylamino-ethyl)-anilino)-1-phenyl-methylene]-6-ethylmethylcarbamoyl-2-indolinone-   (750)    3-Z-[1-(4-dimethylaminomethyl-anilino)-1-phenyl-methylene]-6-ethylmethylcarbamoyl-2-indolinone-   (751)    3-Z-[1-((1-methyl-piperidin-4-yl)-amino-1-phenyl-methylene]-6-ethylmethylcarbamoyl-2-indolinone-   (752)    3-Z-[1-(trans-4-dimethylamino-cyclohexylamino)-1-phenyl-methylene]-6-ethylmethylcarbamoyl-2-indolinone-   (753)    3-Z-[1-(4-(2-diethylamino-ethoxy)-anilino)-1-phenyl-methylene]-6-ethylmethylcarbamoyl-2-indolinone-   (754)    3-Z-[1-(4-(N-(3-dimethylamino-propyl)-N-propionyl-amino)-anilino)-1-phenyl-methylene]-6-ethylmethylcarbamoyl-2-indolinone-   (755)    3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-ethylmethylcarbamoyl-2-indolinone-   (756)    3-Z-[1-cyclohexylamino-1-phenyl-methylene]-6-ethylmethylcarbamoyl-2-indolinone-   (757)    3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-acetyl-amino)-anilino)-1-phenyl-methylene]-6-ethylmethylcarbamoyl-2-indolinone-   (758)    3-Z-[1-(3-diethylaminomethyl-anilino)-1-phenyl-methylene]-6-ethylmethylcarbamoyl-2-indolinone-   (759)    3-Z-[1-(4-(N-dimethylaminomethylcarbonyl-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-ethylmethylcarbamoyl-2-indolinone-   (760)    3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-methylsulphonyl-amino)-anilino)-1-phenyl-methylene]-6-ethylmethylcarbamoyl-2-indolinone-   (761)    3-Z-[1-anilino-1-phenyl-methylene]-6-ethylmethylcarbamoyl-2-indolinone-   (762)    3-Z-[1-(4-ethylaminomethyl-anilino)-1-phenyl-methylene]-6-ethylmethylcarbamoyl-2-indolinone-   (763)    3-Z-[1-(4-((2-diethylamino-ethyl)-anilino)-1-phenyl-methylene]-6-ethylmethylcarbamoyl-2-indolinone-   (764)    3-Z-[1-(4-(N-(3-dimethylamino-propyl)-N-acetyl-amino)-anilino)-1-phenyl-methylene]-6-ethylmethylcarbamoyl-2-indolinone-   (765)    3-Z-[1-(4-(N-methyl-N-methylsulphonyl-amino)-anilino)-1-phenyl-methylene]-6-ethylmethylcarbamoyl-2-indolinone-   (766)    3-Z-[1-(4-methoxycarbonyl-anilino)-1-phenyl-methylene]-6-ethylmethylcarbamoyl-2-indolinone-   (767)    3-Z-[1-(4-carboxy-anilino)-1-phenyl-methylene]-6-ethylmethylcarbamoyl-2-indolinone-   (768)    3-Z-[1-(4-(N-(dimethylamino-carbonylmethyl)-N-methylsulphonyl-amino)-anilino)-1-phenyl-methylene]-6-ethylmethylcarbamoyl-2-indolinone-   (769)    3-Z-[1-(4-(2-dimethylamino-ethoxy)-anilino)-1-phenyl-methylene]-6-ethylcarbamoyl-2-indolinone-   (770)    3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-ethylcarbamoyl-2-indolinone-   (771)    3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-methylsulphonyl-amino)-anilino)-1-phenyl-methylene]-6-ethylcarbamoyl-2-indolinone-   (772)    3-Z-[1-(4-(2-dimethylamino-ethoxy)-anilino)-1-phenyl-methylene]-6-ethylmethylcarbamoyl-2-indolinone-   (773)    3-Z-[1-(4-(N-dimethylaminomethylcarbonyl-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-ethylcarbamoyl-2-indolinone-   (774)    3-Z-[1-(4-dimethylaminomethyl-anilino)-1-phenyl-methylene]-6-ethylcarbamoyl-2-indolinone-   (775)    3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-acetyl-amino)-anilino)-1-phenyl-methylene]-6-ethylcarbamoyl-2-indolinone-   (776)    3-Z-[1-(4-(N-(3-dimethylamino-propyl)-N-acetyl-amino)-anilino)-1-phenyl-methylene]-6-ethylcarbamoyl-2-indolinone-   (777)    3-Z-[1-(4-carbamoyl-anilino)-1-phenyl-methylene]-6-ethylmethylcarbamoyl-2-indolinone-   (778)    3-Z-[1-(4-(N-(2-diethylamino-ethyl)-carbamoyl)-anilino)-1-phenyl-methylene]-6-ethylmethylcarbamoyl-2-indolinone-   (779)    3-Z-[1-(4-((4-methyl-piperazin-1-yl)-carbonyl)-anilino)-1-phenyl-methylene]-6-ethylmethylcarbamoyl-2-indolinone-   (780)    3-Z-[1-(4-((4-methyl-piperazin-1-yl)-carbonyl)-anilino)-1-phenyl-methylene]-6-ethylcarbamoyl-2-indolinone-   (781)    3-Z-[1-(4-((4-ethyl-piperazin-1-yl)-carbonyl)-anilino)-1-phenyl-methylene]-6-ethylmethylcarbamoyl-2-indolinone-   (782)    3-Z-[1-(4-(N-ethyl-N-(2-dimethylamino-ethyl)-carbamoyl)-anilino)-1-phenyl-methylene]-6-ethylmethylcarbamoyl-2-indolinone-   (783)    3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-diethylcarbamoyl-2-indolinone-   (784)    3-Z-[1-(4-((cis-3,5-dimethyl-piperazin-1-yl)-carbonyl)-anilino)-1-phenyl-methylene]-6-ethylmethylcarbamoyl-2-indolinone-   (785)    3-Z-[1-(4-((4-ethyl-piperazin-1-yl)-carbonyl)-anilino)-1-phenyl-methylene]-6-ethylcarbamoyl-2-indolinone-   (786)    3-Z-[1-(4-(N-(2-diethylamino-ethyl)-carbamoyl)-anilino)-1-phenyl-methylene]-6-ethylmethylcarbamoyl-2-indolinone-   (787)    3-Z-[1-(4-((cis-3,5-dimethyl-piperazin-1-yl)-carbonyl)-anilino)-1-phenyl-methylene]-6-ethylcarbamoyl-2-indolinone-   (788)    3-Z-[1-(4-(N-(3-dimethylamino-propyl)-N-methylsulphonyl-amino)-anilino)-1-phenyl-methylene]-6-ethylcarbamoyl-2-indolinone-   (789)    3-Z-[1-(4-(N-dimethylaminomethylcarbonyl-N-methyl-amino)-anilino)-methylene]-6-methoxycarbonyl-2-indolinone-   (790)    3-Z-[1-(4-dimethylaminomethyl-anilino)-methylene]-6-methoxycarbonyl-2-indolinone-   (791)    3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-anilino)-methylene]-6-methoxycarbonyl-2-indolinone-   (792)    3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-anilino)-methylene]-6-ethylcarbamoyl-2-indolinone-   (793)    3-Z-[1-(4-dimethylaminomethyl-anilino)-methylene]-6-ethylcarbamoyl-2-indolinone-   (794)    3-Z-[1-(4-(piperidin-1-yl-methyl)-anilino)-methylene]-6-ethylcarbamoyl-2-indolinone-   (795)    3-Z-[1-(4-(N-(3-dimethylamino-propyl)-N-acetyl-amino)-anilino)-methylene]-6-ethylcarbamoyl-2-indolinone

as well as their tautomers, their stereoisomers or the physiologicallyacceptable salts thereof.

The compounds of general formula I, their tautomers, their stereoisomersor the physiologically acceptable salts thereof are thus suitable forthe prevention or treatment of a specific fibrotic disease selected fromthe group consisting of:

Fibrosis and remodeling of lung tissue in chronic obstructive pulmonarydisease (COPD), chronic bronchitis, and emphysema;

Lung fibrosis and pulmonary diseases with a fibrotic component includingbut not limited to idiopathic pulmonary fibrosis (IPF), giant cellinterstitial pneumonia (GIP), sarcodosis, cystic fibrosis, respiratorydistress syndrome (ARDS), granulomatosis, silicosis, drug-induced lungfibrosis (for example, induced by drugs such as bleomycin,bis-chloronitrosourea, cyclophosphamide, amiodarone, procainamide,penicillamine, gold or nitrofurantoin), silicosis, asbestosis, systemicscleroderma;

Fibrosis and remodeling in asthma;

Fibrosis in rheumatoid arthritis;

Virally induced hepatic cirrhosis, for example hepatitis C;

Radiation-induced fibrosis;

Restenosis, post angioplasty;

Renal disorders including chronic glomerulonephritis, renal fibrosis inpatients receiving cyclosporine and renal fibrosis due to high bloodpressure;

Diseases of the skin with a fibrotic component including but not limitedto, scleroderma, sarcodosis, systemic lupus erythematosus;

Excessive scarring.

In a preferred embodiment in accordance with the present invention, thecompounds of general formula I, their tautomers, their stereoisomers orthe physiologically acceptable salts thereof are especially suitable forthe prevention or treatment of idiopathic pulmonary fibrosis.

BIOLOGICAL ACTIVITY

The following experimental results illustrate the present inventionwithout representing a limitation of its scope.

Example B1

In the following experiments of Example B1, Example A denotes thecompound3-Z-[1-(4-(N-dimethylaminomethylcarbonyl-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone,which is compound (m) of the list of the preferred compounds.

(A) Effect of a representative compound on lung morphology followingbleomycin-induced pulmonary fibrosis.

Materials and Methods

Bleomycin sulfate (Bleomycin HEXAL™) was purchased from a localpharmacy.

Bleomycin Administration and Treatment Protocols

All experiments were performed in accordance with German guidelines foranimal welfare, performed by persons certified to work with animals andapproved by the responsible authorities. Male Wistar rats wereintratracheally injected with Bleomycin sulfate (10 U/kg body weight in300 μl saline) or saline alone (saline control) using a catheter (0.5 mminternal diameter, 1.0 mm external diameter) through the nasal passage,following exposure to the anaesthetic Isofluorane for 5 minutes. Thefollowing day, the rats were orally treated with Example A (compound(m)) or saline suspended in 1 ml 0.1% Natrosol. Control rats wereadministered 1 ml 0.1% Natrosol (vehicle control).

A total of 25 rats were investigated and were grouped and treated asshown in Table 1.

TABLE 1 Intratracheal No. of Treatment instillation animals CompoundSchedule Bleomycin 10 U/kg 10 Example A Days 1-21 (Compound (m))Bleomycin 10 U/kg 10 Vehicle only Days 1-21 Saline (300 μl) 5 Vehicleonly Days 1-21

21 days following bleomycin instillation, the rats were killed with alethal intraperitoneal injection of Narcoren™ (Pentobarbital Sodium,Rhone Merieux). The lungs were then removed, blotted dry and half wassnap frozen in liquid nitrogen and stored at −80° C. The other half wasfixed in 4% formalin for subsequent paraffin embedding and histology.

Histology

The lung tissues fixed in 4% formalin were embedded into paraffin and 5m sections were cut using a microtome (Leica SM200R) and placed onpoly-L-lysine coated slides. The sections were then dried onto theslides (60° C. 2 hours) and then left to cool at room temperature.Collagen deposition was assessed using Masson's Trichrome staining.

Results

FIG. 1A shows the result obtained with the control group, which receivedsaline and the vehicle instead of bleomycin intratracheally.

Rats treated intratracheally with bleomycin and the vehicle developedsevere lung fibrosis, as seen in FIG. 1B. The alveoli have been largelyreplaced by fibroblasts and extracellular matrix and the normal lungstructure is nearly obliterated.

Daily treatment of bleomycin-treated rats with 50 mg/kg of Example A(compound (m)) showed a consistent, nearly complete reversal of lungfibrosis in this model. A typical example is shown in FIG. 1C. Alveoliare intact and little or no fibroblast infiltration or extracellularmatrix deposition has occurred. Normal lung structure has beenmaintained, which is evidenced by a comparison of FIG. 1C with FIG. 1A.

(B) Effect of a representative compound on expression of fibrotic markergenes following bleomycin-induced pulmonary fibrosis.

mRNA Extractions and Synthesis of cDNA

One part of the frozen lung tissue dedicated to investigation of geneexpression was cut into small pieces using a sterile scalpel blade.Approximately 100 mg of tissue was then placed into a 2 ml Eppendorftube and 1.5 ml of Trizol (Invitrogen) was added. A sterile tungstencarbide bead (Qiagen) was then added to the tube and the tube was placedin a Retsch MM300 Tissue disruptor (Qiagen) at a frequency of 30.0 Hzfor 8 minutes. After this time, the bead was removed and the samplecentrifuged at 12000 rpm for 10 minutes to remove tissue debris. The RNAwas extracted using a modified version of the manufacturer's protocolsupplied with Trizol. Briefly, 0.3 ml chloroform was added to the tubeand the tube shaken vigorously and then left to incubate at roomtemperature for 5 minutes, after which the tube was centrifuged for 15minutes at 12000 rpm at 4° C. The upper colorless aqueous phase was thencollected and added to 750 μl isopropanol. This was then shakenvigorously and stored at −80° C. overnight. The samples were thenincubated at room temperature for 15 minutes, after which they werecentrifuged for 40 minutes at 12000 rpm at 4° C. The supernatant wasthen removed and 500 μl of 70% ethanol was added to wash the pellet thenthe sample was centrifuged for 10 minutes at 12000 rpm an 4° C., thiswash step was repeated twice, after which the pellet was left to dry for10-15 minutes. Finally the pellet was resuspended in 20 μl RNase freewater and stored at −80° C. The concentration of each sample was thenmeasured using a spectrophotometer.

Using the Superscript™ III (Invitrogen, Paisley, UK) RT-first strandsynthesis kit, 2 μg of each mRNA sample was reversed transcribed using amodified version of the manufacturer's protocol. Briefly, a mixture of 2μg RNA, 1 μl random hexamer primers (50 ng/μl), 1 μl dNTP mix (10 mM)was made up to 10 μl with DEPC-treated water and incubated at 65° C. for5 minutes, after which it was placed on ice for 5 minutes. Followingthis, to each reaction, 2 μl RT buffer (10×), 4 μl MgCl₂ (25 mM), 2 μlDTT (0.1M), 1 μl RNaseOUT™ (40 U/μl) and 1 μl SuperScript™ III enzyme(200 U/μl) was added and the mixture placed in a thermal cycler (AppliedBiosystems) under the following conditions: 25° C. for 10 minutes, 50°C. for 50 minutes and 85° C. for 5 minutes, after which 1 μl of RNase Hwas added and incubated at 37° C. for 20 minutes. The synthesized cDNAwas diluted to 5 ng/μl using the assumption that the RT reaction fullytranscribed all of the mRNA to cDNA and was a concentration of 100ng/μl.

Investigation of Gene Expression Using Real Time PCR

Gene expression was investigated in each of the samples using theApplied Biosystems 7700 sequence detection system. Primers for the 18Sendogenous control and TGFb1 were purchased as pre-developed assayreagent kits, whereas primers and probes (see Table 2 below) forpro-collagen I and fibronectin were designed using PrimerExpress™(Applied Biosystems), ensuring that at least one of the primers orprobes in each set overlapped an intron/exon junction, thus eliminatingthe possibility of amplifying any contaminating genomic DNA in the cDNAsample. The purchased PDARs also amplified only cDNA.

TABLE 2 Target Sequence Fibronectin Forward 5′-GAT GCC GAT CAG AAGTTT GGA-3′ Reverse 5′-TCG TTG GTC GTG CAG ATC TC-3′ Probe5′-FAM-CTG CCC AAT GGC TGC CCA TGA-TAMRA-3′ Pro- Forward5′-CAG ACT GGC AAC CTG Collagen I AAG AAG TC-3′ Reverse5′-TCG CCC CTG AGC TCG AT-3′ Probe 5′-FAM-CTG CTC CTC CAGGGC TCC AAC GA-TAMRA3′

Real Time PCR was carried out in 25 μl reactions, using 25 ng (5 μl) ofcDNA per reaction. A quantitative PCR core kit was purchased(Eurogentec) and a master-mix was made up as follows for 100 reactions:500 μl 10× reaction buffer, 500 μl MgCl₂ (50 mM), 200 μl dNTP mixsolution (5 mM), 25 μl Hot Goldstar enzyme, 75 μl 18S PDAR, 22.5 μlforward primer, 22.5 μl reverse primer, 15 μl probe and 640 μl DEPCtreated water. 20 μl of this master-mix was then added to 25ng (5 μl)target cDNA. Each analysis was carried out in triplicate.

In order to quantify the gene expression, a standard curve wasconstructed for each primer set and was included on each plate. Thestandards were made up of a mix of all the cDNA's under investigation;this mix of cDNA's was serially diluted 10, 20, 50, 100, 100 times. Astandard curve was constructed of the obtained C_(T) (Cycle at whichamplification reaches a set Threshold) against the LOG₁₀ of the dilutionfactor. Curves were drawn for the target gene and the 18S rRNAendogenous control. The C_(T) value for both targets for each of thesamples was then converted to a fold dilution using the standard curveand the target gene value was normalized to the 18S gene value.

Statistics

All statistical analyses were carried out using GraphPad Prism V 4.02software. Comparisons were made using a non-parametric T-test(Mann-Whitney U test) and a significant value was considered to bep·0.05.

Results

The results are shown in FIGS. 2 (procollagen I) and 3 (fibronectin).Each data point represents RNA isolated from the lung of a single rat.

Intratracheal administration of bleomycin and subsequent treatment withvehicle only showed large increases in procollagen I and fibronectingene expression in the lung, as seen in FIGS. 2 and 3, consistent withthe histologically apparent lung fibrosis seen in FIG. 1B.

Daily treatment of Bleomycin-treated rats with 50 mg/kg of Example A(compound (m)) showed a significant (p≤0.0001) inhibition of expressionof fibrotic marker genes in this model, as seen in FIGS. 2 and 3.

This experiment thus demonstrates that expression of fibrotic markers,and therefore deposition of extracellular matrix, may be dramaticallyreduced by treatment with Example A (compound (m)).

Example B2

In the following experiments of Example B2, the compound3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone,which is compound (u) of the list of the preferred compounds, was used.

All the methods employed are the same as the methods described in theexperiments of Example B1, however using compound (u) instead ofcompound (m).

(A) Effect of a representative compound on lung morphology followingbleomycin-induced pulmonary fibrosis.

Samples were prepared from rats treated as outlined in above Table 1 ofexperimental Example B1 (A).

Results

FIG. 4A shows the result obtained with the control group, which receivedsaline and the vehicle instead of bleomycin intratracheally.

Rats treated intratracheally with bleomycin and the vehicle developedsevere lung fibrosis, as seen in FIG. 4B. The alveoli have been largelyreplaced by fibroblasts and extracellular matrix and the normal lungstructure is nearly obliterated.

Daily treatment of bleomycin-treated rats with 50 mg/kg of compound (u)showed a consistent, nearly complete reversal of lung fibrosis in thismodel. A typical example is shown in FIG. 4C. Alveoli are intact andlittle or no fibroblast infiltration or extracellular matrix depositionhas occurred. Normal lung structure has been maintained, which isevidenced by a comparison of FIG. 4C with FIG. 4A.

(B) Effect of a representative compound on expression of fibrotic markergenes following Bleomycin-induced pulmonary fibrosis.

The experiment was carried out using the methods as outlined above forExample B1 (B).

The results are shown in FIG. 5 (procollagen I) and FIG. 6 (TGFb). Eachdata point represents RNA isolated from the lung of a single rat.

Intratracheal administration of bleomycin and subsequent treatment withvehicle only showed large increases in procollagen I and TGFb geneexpression in the lung, as seen in FIGS. 5 and 6, consistent with thehistologically apparent lung fibrosis seen in FIG. 1B.

Daily treatment of bleomycin-treated rats with 50 mg/kg of (compound (u)showed a significant (p<0.0001) inhibition of expression of fibroticmarker genes in this model, as seen in FIGS. 5 and 6.

This experiment also demonstrates that expression of fibrotic markers,and therefore deposition of extracellular matrix, may be dramaticallyreduced by treatment with another compound representative of thisinvention, namely compound (u).

By reason of their biological properties the compounds according to theinvention may be used in monotherapy or in conjunction with otherpharmacologically active compounds. Such pharmacologically activecompounds may be compounds which are, for example, alsopharmacologically active in the treatment of fibrosis. Suchpharmacologically active compounds may also be substances with asecretolytic, broncholytic and/or anti-inflammatory activity.

In a preferred embodiment in accordance with the present invention, suchpharmacologically active compounds are preferably selected from thegroup consisting of anticholinergic agents, beta-2 mimetics, steroids,PDE-IV inhibitors, p38 MAP kinase inhibitors, NK₁ antagonists, LTD4antagonists, EGFR inhibitors and endothelin-antagonists.

Anticholinergic agents may preferably be selected from the groupconsisting of the tiotropium salts, oxitropium salts, flutropium salts,ipratropium salts, glycopyrronium salts and trospium salts.

Beta-2 mimetics may preferably be selected from the beta-2 mimeticsdisclosed, for example, in U.S. Pat. No. 4,460,581, which isincorporated herein by reference.

PDE-IV inhibitors may preferably be selected from the group consistingof enprofyllin, theophyllin, roflumilast, ariflo (cilomilast),CP-325,366, BY343, D-4396 (Sch-351591), AWD-12-281 (GW-842470),N-(3,5-dichloro-1-oxo-pyridin-4-yl)-4-difluoromethoxy-3-cyclopropylmethoxybenzamide,NCS-613, pumafentine,(−)p-[(4aR*,10bS*)-9-ethoxy-1,2,3,4,4a,10b-hexahydro-8-methoxy-2-methylbenzo[s][1,6]naphthyridin-6-yl]-N,N-diisopropylbenzamide,(R)-(+)-1-(4-bromobenzyl)-4-[(3-cyclopentyloxy)-4-methoxyphenyl]-2-pyrrolidone,3-(cyclopentyloxy-4-methoxyphenyl)-1-(4-N′—[N-2-cyano-S-methyl-isothioureido]benzyl)-2-pyrrolidone,cis[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carbonicacid],2-carbomethoxy-4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-1-one,cis[4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-1-ol],(R)-(+)-ethyl[4-(3-cyclopentyloxy-4-methoxyphenyl)pyrrolidin-2-yliden]acetate,(S)-(−)-ethyl[4-(3-cyclopentyloxy-4-methoxyphenyl)pyrrolidin-2-yliden]acetate,CDP840, Bay-198004, D-4418, PD-168787, T-440, T-2585, arofyllin,atizoram, V-11294A, Cl-1018, CDC-801, CDC-3052, D-22888, YM-58997,Z-15370,9-cyclopentyl-5,6-dihydro-7-ethyl-3-(2-thienyl)-9H-pyrazolo[3,4-c]-1,2,4-triazolo[4,3-a]pyridineand9-cyclopentyl-5,6-dihydro-7-ethyl-3-(tert-butyl)-9H-pyrazolo[3,4-c]-1,2,4-triazolo[4,3-a]pyridine.These compounds may be used, as available, in the form of theirracemates, enantiomers or diastereoisomers, or in the form ofpharamacologically acceptable acid addition salts thereof, or in theform of their solvates and/or hydrates.

Steroids may preferably be selected from the group consisting ofprednisolone, prednisone, butixocortpropionate, RPR-106541, flunisolid,beclomethasone, triamcinolone, budesonid, fluticasone, mometasone,ciclesonid, rofleponid, ST-126, dexamethasone,6α,9α-difluoro-17α-[(2-furanylcarbonyl)oxy]-11β-hydroxy-16α-methyl-3-oxo-androsta-1,4-dien-17β-carbothionicacid (S)-fluoromethylester, and6α,9α-difluoro-11β-hydroxy-16α-methyl-3-oxo-17α-propionyloxy-androsta-1,4-diene-17β-carbothionicacid (S)-(2-oxo-tetrahydro-furan-3S-yl)ester. These compounds may beused, as available, in the form of their racemates, enantiomers ordiastereoisomers, or in the form of pharamacologically acceptable acidaddition salts thereof, or in the form of their solvates and/orhydrates.

p38 MAP kinase inhibitors may preferably be selected from the groupconsisting of the p38 Kinase inhibitors that are disclosed for instancein U.S. Pat. No. 5,716,972, U.S. Pat. No. 5,686,455, U.S. Pat. No.5,656,644, U.S. Pat. No. 5,593,992, U.S. Pat. No. 5,593,991, U.S. Pat.No. 5,663,334, U.S. Pat. No. 5,670,527, U.S. Pat. Nos. 5,559,137,5,658,903, U.S. Pat. No. 5,739,143, U.S. Pat. No. 5,756,499, U.S. Pat.No. 6,277,989, U.S. Pat. No. 6,340,685, and U.S. Pat. No. 5,716,955 andPCT applications WO 92/12154, WO 94/19350, WO 95/09853, WO 95/09851, WO95/09847, WO 95/09852, WO 97/25048, WO 97/25047, WO 97/33883, WO97/35856, WO 97/35855, WO 97/36587, WO 97/47618, WO 97/16442, WO97/16441, WO 97/12876, WO 98/25619, WO 98/06715, WO 98/07425, WO98/28292, WO 98/56377, WO 98/07966, WO 98/56377, WO 98/22109, WO98/24782, WO 98/24780, WO 98/22457, WO 98/52558, WO 98/52559, WO98/52941, WO 98/52937, WO 98/52940, WO 98/56788, WO 98/27098, WO98/47892, WO 98/47899, WO 98/50356, WO 98/32733, WO 99/58523, WO99/01452, WO 99/01131, WO 99/01130, WO 99/01136, WO 99/17776, WO99/32121, WO 99/58502, WO 99/58523, WO 99/57101, WO 99/61426, WO99/59960, WO 99/59959, WO 99/00357, WO 99/03837, WO 99/01441, WO99/01449, WO 99/03484, WO 99/15164, WO 99/32110, WO 99/32111, WO99/32463, WO 99/64400, WO 99/43680, WO 99/17204, WO 99/25717, WO99/50238, WO 99/61437, WO 99/61440, WO 00/26209, WO 00/18738, WO00/17175, WO 00/20402, WO 00/01688, WO 00/07980, WO 00/07991, WO00/06563, WO 00/12074, WO 00/12497, WO 00/31072, WO 00/31063, WO00/23072, WO 00/31065, WO 00/35911, WO 00/39116, WO 00/43384, WO00/41698, WO 00/69848, WO 00/26209, WO 00/63204, WO 00/07985, WO00/59904, WO 00/71535, WO 00/10563, WO 00/25791, WO 00/55152, WO00/55139, WO 00/17204, WO 00/36096, WO 00/55120, WO 00/55153, WO00/56738, WO 01/21591, WO 01/29041, WO 01/29042, WO 01/62731, WO01/05744, WO 01/05745, WO 01/05746, WO 01/05749, WO 01/05751, WO01/27315, WO 01/42189, WO 01/00208, WO 01/42241, WO 01/34605, WO01/47897, WO 01/64676, WO 01/37837, WO 01/38312, WO 01/38313, WO01/36403, WO 01/38314, WO 01/47921, WO 01/27089, DE 19842833, and JP2000 86657 whose disclosures are all incorporated herein by reference intheir entirety.

Of particular interest for the combinations according to the inventionare those p38 inhibitors disclosed in U.S. Pat. No. 6,277,989, U.S. Pat.No. 6,340,685, WO 00/12074, WO 00/12497, WO 00/59904, WO 00/71535, WO01/64676, WO 99/61426, WO 00/10563, WO 00/25791, WO 01/37837, WO01/38312, WO 01/38313, WO 01/38314, WO 01/47921, WO 99/61437, WO99/61440, WO 00/17175, WO 00/17204, WO 00/36096, WO 98/27098, WO99/00357, WO 99/58502, WO 99/64400, WO 99/01131, WO 00/43384, WO00/55152, WO 00/55139, and WO 01/36403. In a preferred embodiment thep38 kinase inhibitor is selected from the compounds of following formula(I) as disclosed in WO 99/01131

wherein

R₁ is 4-pyridyl, pyrimidinyl, 4-pyridazinyl, 1,2,4-triazin-5-yl,quinolyl, isoquinolinyl, or quinazolin-4-yl ring, which ring issubstituted with Y—R_(a) and optionally with an additional independentsubstituent selected from C₁₋₄ alkyl, halogen, hydroxyl, C₁₋₄ alkoxy,C₁₋₄ akylthio, C₁₋₄ aklylsulfinyl, CH₂OR₁₂, amino, mono and di-C₁₋₆alkyl substituted amino, an N-heterocyclyl ring which ring has from 5 to7 members and optionally contains an additional heteroatom selected fromoxygen, sulfur or NR₁₅, N(R₁₀)C(O)R_(b) or NHR_(a);

Y is oxygen or sulfur;

R₄ is phenyl, naphth-1-yl or naphthyl, or a heteroaryl, which isoptionally substituted by one or two substituents, each of which isindependently selected, and which, for a 4-phenyl, 4naphth-1-yl,5-naphth-2-yl or 6-naphth-2-yl substituent, is halogen, cyano, nitro,C(Z)NR₇R₁₇, C(Z)OR₁₆, (CR₁₀R₂₀)_(v)COR₁₂, SR₅, SOR₅, OR₁₂,halo-substituted-C₁₋₄ alkyl, C₁₋₄ alkyl, ZC(Z)R₁₂, NR₁₀C(Z)R₁₆, or(CR₁₀R₂₀)_(v)NR₁₀R₂₀ and which, for other positions of substitution, ishalogen, cyano, C(Z)NR₁₃R₁₄, C(Z)OR₃, (CR₁₀R₂₀)_(m)COR₃, S(O)_(m)R₃,OR₃, halo-substituted-C₁₋₄ alkyl, C₁₋₄ alkyl, (CR₁₀R₂₀)_(m″)R₁₀C(Z)R₃,NR₁₀S(O)_(m′)R₈, NR₁₀S(O)_(m′)NR₇R₁₇, ZC(Z)R₃ or (CR₁₀R₂₀)_(m″)NR₁₃R₁₄;

Z is oxygen or sulfur;

n is an integer having a value of 1 to 10;

m is 0, or integer 1 or 2;

m′ is an integer having a value of 1 or 2;

m″ is 0, or an integer having a value of 1 to 5;

v is 0, or an integer having a value of 1 to 2;

R₂ is —C(H)(A)(R₂₂);

A is optionally substituted aryl, heterocyclyl, or heteroaryl ring, or Ais substituted C₁₋₁₀ alkyl;

R₂₂ is an optionally substituted C₁₋₁₀ alkyl;

R_(a) is aryl, arylC₁₋₆ alkyl, heterocyclic, heterocyclylC₁₋₆ alkyl,heteroaryl, heteroarylC₁₋₆alkyl, wherein each of these moieties may beoptionally substituted;

R_(b) is hydrogen, C₁₋₆ alkyl, C₃₋₇ cycloalkyl, aryl, aryl C₁₋₄ alkyl,heteroaryl, heteroarylC₁₋₄ alkyl, heterocyclyl, or heterocyclylC₁₋₄alkyl, wherein each of these moieties may be optionally substituted;

R₃ is heterocyclyl, heterocyclyl C₁₋₁₀ alkyl or R₈;

R₅ is hydrogen, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl or NR₇R₁₇,excluding the moieties SR₅ being SNR₇R₁₇ and SOR₅ being SOH;

R₆ is hydrogen, a pharmaceutically acceptable cation, C₁₋₁₀ alkyl, C₃₋₇cycloalkyl, aryl, aryl C₁₋₄ alkyl, heteroaryl, heteroaryl C₁₋₄ alkyl,heterocyclyl, aryl, or C₁₋₁₀ alkanoyl;

R₇ and R₁₇ is each independently selected from hydrogen or C₁₋₄ alkyl orR₇ and R₁₇ together with the nitrogen to which they are attached form aheterocyclic ring of 5 to 7 members which ring optionally contains anadditional heteroatom selected from oxygen, sulfur or NR₁₅;

R₈ is C₁₋₁₀ alkyl, halo-substituted C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀alkynyl, C₃₋₇ cycloalkyl, C₅₋₇ cycloalkenyl, aryl, aryl C₁₋₁₀ alkyl,heteroaryl, heteroaryl C₁₋₁₀ alkyl, (CR₁₀R₂₀)_(n)OR₁₁,(CR₁₀R₂₀)_(n)S(O)_(m)R₁₈, (CR₁₀R₂₀)_(n)NHS(O)₂R₁₈, (CR₁₀R₂₀)_(n)NR₁₃R₁₄;wherein the aryl, arylalkyl, heteroaryl, heteroaryl alkyl may beoptionally substituted;

R₉ is hydrogen, C(Z) R₁₁ or optionally substituted C₁₋₁₀ alkyl,S(O)₂R₁₈, optionally substituted aryl or optionally substituted arylC₁₋₄ alkyl;

R₁₀ and R₂₀ is each independently selected from hydrogen or C₁₋₄ alkyl;

R₁₁ is hydrogen, C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, heterocyclyl,heterocyclyl C₁₋₁₀ alkyl, aryl, arylC₁₋₁₀ alkyl, heteroaryl orheteroaryl C₁₋₁₀ alkyl, wherein these moieties may be optionallysubstituted;

R₁₂ is hydrogen or R₁₆;

R₁₃ an R₁₄ is each independently selected from hydrogen or optionallysubstituted C₁₋₄ alkyl, optionally substituted aryl or optionallysubstituted arylC₁₋₄ alkyl, or together with the nitrogen which they areattached form a heterocyclic ring of 5 to 7 members which ringoptionally contains an additional heteroatom selected from oxygen,sulfur or NR₉;

R₁₅ is R₁₀ or C(Z)—C₁₋₄ alkyl;

R₁₆ is C₁₋₄ alkyl, halo-substituted-C₁₋₄ alkyl, or C₃₋₇ cycloalkyl;

R₁₈ is C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, heterocyclyl, aryl, aryl₁₋₁₀alkyl,heterocyclyl, heterocyclyl-C₁₋₁₀alkyl, heteroaryl or heteroaryl₁₋₁₀alkyl;

-   -   or a pharmaceutically acceptable salt thereof.

NK1 antagonists may preferably be selected from the group consisting ofN-[2-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-2-{4-cyclopropylmethyl-piperazin-1-yl}-N-methyl-2-phenyl-acetamide(BIIF 1149), CP-122721, FK-888, NKP 608C, NKP 608A, CGP 60829, SR 48968(Saredutant), SR 140333 (Nolpitantium besilate/chloride), LY 303 870(Lanepitant), MEN-11420 (Nepadutant), SB 223412, MDL-105172A,MDL-103896, MEN-11149, MEN-11467, DNK 333A, SR-144190, YM-49244,YM-44778, ZM-274773, MEN-10930, S-19752, Neuronorm, YM-35375, DA-5018,Aprepitant (MK-869), L-754030, CJ-11974, L-758298, DNK-33A, 6b-I,CJ-11974, TAK-637, GR 205171 and the arylglycine amide derivates ofgeneral formula (VIII)

wherein

R¹ and R² together with the N-atom they are bound to form a ring offormula

wherein r and s independently denote the number 2 or 3;

R⁶ denotes H, —C₁-C₅-alkyl, C₃-C₅-alkenyl, propinyl,hydroxy(C₂-C₄)alkyl, methoxy(C₂-C₄)alkyl,di(C₁-C₃)alkylamino(C₂-C₄)alkyl, amino(C₂-C₄)alkyl, amino,di(C₁-C₃)alkylamino, monofluoro-up to perfluoro(C₁-C₂)alkyl,N-methylpiperidinyl, pyridyl, pyrimidinyl, pyrazinyl or pyridazinyl,

R⁷ denotes any of the groups defined under (a) to (d):

-   -   (a) hydroxy    -   (b) 4-piperidinopiperidyl,

-   -   -   wherein R¹⁶ and R¹⁷ independently denote H, (C₁-C₄)alkyl,            (C₃-C₆)cycloalkyl, hydroxy(C₂-C₄)alkyl,            dihydroxy(C₂-C₄)alkyl, (C₁-C₃)alkoxy(C₂-C₄)alkyl,            phenyl(C₁-C₄)alkyl or di(C₁-C₃)alkylamino(C₂-C₄)alkyl, and

R⁸ denotes H,

optionally in the form of enantiomers, mixtures of enantiomers or theracemates.

The compounds of formula (VIII) mentioned hereinbefore are described inWO 96/32386, WO 97/32865 and WO 02/32865. The disclosure of theseinternational patent applications is incorporated herein by reference inits entirety.

LTD4 antagonists may preferably be selected from the group consisting ofmontelukast,1-(((R)-(3-(2-(6,7-difluoro-2-quinolinyl)ethenyl)phenyl)-3-(2-(2-hydroxy-2-propyl)phenyl)thio)methylcyclopropane-acetate,1-(((1(R)-3(3-(2-(2,3-dichlorothieno[3,2-b]pyridin-5-yl)-(E)-ethenyl)phenyl)-3-(2-(1-hydroxy-1-methylethyl)phenyl)propyl)thio)methyl)cyclopropane-acetate,pranlukast, zafirlukast,[2-[[2-(4-tert-butyl-2-thiazolyl)-5-benzofuranyl]oxymethyl]phenyl]acetate,MCC-847 (ZD-3523), MN-001, MEN-91507 (LM-1507), VUF-5078, VUF-K-8707 andL-733321. These compounds may be used, as available, in the form oftheir racemates, enantiomers or diastereoisomers, or in the form ofpharamacologically acceptable acid addition salts thereof, or in theform of their solvates and/or hydrates.

EGFR inhibitors may preferably be selected from the group consisting of4-[(3-chlor-4-fluorphenyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-chinazoline,4-[(3-chlor-4-fluorphenyl)amino]-6-{[4-(N,N-diethylamino)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-chinazoline,4-[(3-chlor-4-fluorphenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-chinazoline,4-[(R)-(1-phenyl-ethyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopentyloxy-chinazoline,4-[(3-chlor-4-fluor-phenyl)amino]-6-{[4-((R)-6-methyl-2-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-chinazoline,4-[(3-chlor-4-fluor-phenyl)amino]-6-{[4-((R)-6-methyl-2-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-[(S)-(tetrahydrofuran-3-yl)oxy]-chinazoline,4-[(3-chlor-4-fluor-phenyl)amino]-6-{[4-((R)-2-methoxymethyl-6-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-chinazoline,4-[(3-chlor-4-fluor-phenyl)amino]-6-[2-((S)-6-methyl-2-oxo-morpholin-4-yl)-ethoxy]-7-methoxy-chinazoline,4-[(3-chlor-4-fluorphenyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-methyl-amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxy-chinazoline,4-[(3-chlor-4-fluorphenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-cyclopentyloxy-chinazoline,4-[(R)-(1-phenyl-ethyl)amino]-6-{[4-(N,N-bis-(2-methoxy-ethyl)-amino)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-chinazoline,4-[(R)-(1-phenyl-ethyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-ethyl-amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxy-chinazoline,4-[(R)-(1-phenyl-ethyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-methyl-amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxy-chinazoline,4-[(R)-(1-phenyl-ethyl)amino]-6-({4-[N-(tetrahydropyran-4-yl)-N-methyl-amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxy-chinazoline,4-[(3-chlor-4-fluorphenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-((R)-tetrahydrofuran-3-yloxy)-chinazoline,4-[(3-chlor-4-fluorphenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-((S)-tetrahydrofuran-3-yloxy)-chinazoline,4-[(3-chlor-4-fluorphenyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-methyl-amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopentyloxy-chinazoline,4-[(3-chlor-4-fluorphenyl)amino]-6-{[4-(N-cyclopropyl-N-methyl-amino)-1-oxo-2-buten-1-yl]amino}-7-cyclopentyloxy-chinazoline,4-[(3-chlor-4-fluorphenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-[(R)-(tetrahydrofuran-2-yl)methoxy]-chinazoline,4-[(3-chlor-4-fluorphenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-[(S)-(tetrahydrofuran-2-yl)methoxy]-chinazoline,4-[(3-ethinyl-phenyl)amino]-6,7-bis-(2-methoxy-ethoxy)-chinazoline,4-[(3-chlor-4-fluorphenyl)amino]-7-[3-(morpholin-4-yl)-propyloxy]-6-[(vinylcarbonyl)amino]-chinazoline,4-[(R)-(1-phenyl-ethyl)amino]-6-(4-hydroxy-phenyl)-7H-pyrrolo[2,3-d]pyrimidine,3-cyano-4-[(3-chlor-4-fluorphenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-ethoxy-chinoline,4-{[3-chlor-4-(3-fluor-benzyloxy)-phenyl]amino}-6-(5-{[(2-methansulfonyl-ethyl)amino]methyl}-furan-2-yl)chinazoline,4-[(R)-(1-phenyl-ethyl)amino]-6-{[4-((R)-6-methyl-2-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-methoxy-chinazoline,4-[(3-chlor-4-fluorphenyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-[(tetrahydrofuran-2-yl)methoxy]-chinazoline,4-[(3-chlor-4-fluorphenyl)amino]-6-({4-[N,N-bis-(2-methoxy-ethyl)-amino]-1-oxo-2-buten-1-yl}amino)-7-[(tetrahydrofuran-2-yl)methoxy]-chinazoline,4-[(3-ethinyl-phenyl)amino]-6-{[4-(5,5-dimethyl-2-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-chinazoline,4-[(3-chlor-4-fluor-phenyl)amino]-6-[2-(2,2-dimethyl-6-oxo-morpholin-4-yl)-ethoxy]-7-methoxy-chinazoline,4-[(3-chlor-4-fluor-phenyl)amino]-6-[2-(2,2-dimethyl-6-oxo-morpholin-4-yl)-ethoxy]-7-[(R)-(tetrahydrofuran-2-yl)methoxy]-chinazoline,4-[(3-chlor-4-fluor-phenyl)amino]-7-[2-(2,2-dimethyl-6-oxo-morpholin-4-yl)-ethoxy]-6-[(S)-(tetrahydrofuran-2-yl)methoxy]-chinazoline,4-[(3-chlor-4-fluor-phenyl)amino]-6-{2-[4-(2-oxo-morpholin-4-yl)-piperidin-1-yl]-ethoxy}-7-methoxy-chinazoline,4-[(3-chlor-4-fluor-phenyl)amino]-6-[1-(tert.-butyloxycarbonyl)-piperidin-4-yloxy]-7-methoxy-chinazoline,4-[(3-chlor-4-fluor-phenyl)amino]-6-(trans-4-amino-cyclohexan-1-yloxy)-7-methoxy-chinazoline,4-[(3-chlor-4-fluor-phenyl)amino]-6-(trans-4-methansulfonylamino-cyclohexan-1-yloxy)-7-methoxy-chinazoline,4-[(3-chlor-4-fluor-phenyl)amino]-6-(tetrahydropyran-3-yloxy)-7-methoxy-chinazoline,4-[(3-chlor-4-fluor-phenyl)amino]-6-(1-methyl-piperidin-4-yloxy)-7-methoxy-chinazoline,4-[(3-chlor-4-fluor-phenyl)amino]-6-{1-[(morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-chinazoline,4-[(3-chlor-4-fluor-phenyl)amino]-6-{1-[(methoxymethyl)carbonyl]-piperidin-4-yloxy}-7-methoxy-chinazoline,4-[(3-chlor-4-fluor-phenyl)amino]-6-(piperidin-3-yloxy)-7-methoxy-chinazoline,4-[(3-chlor-4-fluor-phenyl)amino]-6-[1-(2-acetylamino-ethyl)-piperidin-4-yloxy]-7-methoxy-chinazoline,4-[(3-chlor-4-fluor-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-ethoxy-chinazoline,4-[(3-chlor-4-fluor-phenyl)amino]-6-((S)-tetrahydrofuran-3-yloxy)-7-hydroxy-chinazoline,4-[(3-chlor-4-fluor-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2-methoxy-ethoxy)-chinazoline,4-[(3-chlor-4-fluor-phenyl)amino]-6-{trans-4-[(dimethylamino)sulfonylamino]-cyclohexan-1-yloxy}-7-methoxy-chinazoline,4-[(3-chlor-4-fluor-phenyl)amino]-6-{trans-4-[(morpholin-4-yl)carbonylamino]-cyclohexan-1-yloxy}-7-methoxy-chinazoline,4-[(3-chlor-4-fluor-phenyl)amino]-6-{trans-4-[(morpholin-4-yl)sulfonylamino]-cyclohexan-1-yloxy}-7-methoxy-chinazoline,4-[(3-chlor-4-fluor-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2-acetylamino-ethoxy)-chinazoline,4-[(3-chlor-4-fluor-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2-methansulfonylamino-ethoxy)-chinazoline,4-[(3-chlor-4-fluor-phenyl)amino]-6-{1-[(piperidin-1-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-chinazoline,4-[(3-chlor-4-fluor-phenyl)amino]-6-(1-aminocarbonylmethyl-piperidin-4-yloxy)-7-methoxy-chinazoline,4-[(3-chlor-4-fluor-phenyl)amino]-6-(cis-4-{N-[(tetrahydropyran-4-yl)carbonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-chinazoline,4-[(3-chlor-4-fluor-phenyl)amino]-6-(cis-4-{N-[(morpholin-4-yl)carbonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-chinazoline,4-[(3-chlor-4-fluor-phenyl)amino]-6-(cis-4-{N-[(morpholin-4-yl)sulfonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-chinazoline,4-[(3-chlor-4-fluor-phenyl)amino]-6-(trans-4-ethansulfonylamino-cyclohexan-1-yloxy)-7-methoxy-chinazoline,4-[(3-chlor-4-fluor-phenyl)amino]-6-(1-methansulfonyl-piperidin-4-yloxy)-7-ethoxy-chinazoline,4-[(3-chlor-4-fluor-phenyl)amino]-6-(1-methansulfonyl-piperidin-4-yloxy)-7-(2-methoxy-ethoxy)-chinazoline,4-[(3-chlor-4-fluor-phenyl)amino]-6-[1-(2-methoxy-acetyl)-piperidin-4-yloxy]-7-(2-methoxy-ethoxy)-chinazoline,4-[(3-chlor-4-fluor-phenyl)amino]-6-(cis-4-acetylamino-cyclohexan-1-yloxy)-7-methoxy-chinazoline,4-[(3-Ethinyl-phenyl)amino]-6-[1-(tert.-butyloxycarbonyl)-piperidin-4-yloxy]-7-methoxy-chinazoline,4-[(3-Ethinyl-phenyl)amino]-6-(tetrahydropyran-4-yloxy]-7-methoxy-chinazoline,4-[(3-chlor-4-fluor-phenyl)amino]-6-(cis-4-{N-[(piperidin-1-yl)carbonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-chinazoline,4-[(3-chlor-4-fluor-phenyl)amino]-6-(cis-4-{N-[(4-methyl-piperazin-1-yl)carbonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-chinazoline,4-[(3-chlor-4-fluor-phenyl)amino]-6-{cis-4-[(morpholin-4-yl)carbonylamino]-cyclohexan-1-yloxy}-7-methoxy-chinazoline,4-[(3-chlor-4-fluor-phenyl)amino]-6-{1-[2-(2-oxopyrrolidin-1-yl)ethyl]-piperidin-4-yloxy}-7-methoxy-chinazoline,4-[(3-chlor-4-fluor-phenyl)amino]-6-{1-[(morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-(2-methoxy-ethoxy)-chinazoline,4-[(3-Ethinyl-phenyl)amino]-6-(1-acetyl-piperidin-4-yloxy)-7-methoxy-chinazoline,4-[(3-Ethinyl-phenyl)amino]-6-(1-methyl-piperidin-4-yloxy)-7-methoxy-chinazoline,4-[(3-Ethinyl-phenyl)amino]-6-(1-methansulfonyl-piperidin-4-yloxy)-7-methoxy-chinazoline,4-[(3-chlor-4-fluor-phenyl)amino]-6-(1-methyl-piperidin-4-yloxy)-7(2-methoxy-ethoxy)-chinazoline,4-[(3-chlor-4-fluor-phenyl)amino]-6-(1-isopropyloxycarbonyl-piperidin-4-yloxy)-7-methoxy-chinazoline,4-[(3-chlor-4-fluor-phenyl)amino]-6-(cis-4-methylamino-cyclohexan-1-yloxy)-7-methoxy-chinazoline,4-[(3-chlor-4-fluor-phenyl)amino]-6-{cis-4-[N-(2-methoxy-acetyl)-N-methyl-amino]-cyclohexan-1-yloxy}-7-methoxy-chinazoline,4-[(3-Ethinyl-phenyl)amino]-6-(piperidin-4-yloxy)-7-methoxy-chinazoline,4-[(3-Ethinyl-phenyl)amino]-6-[1-(2-methoxy-acetyl)-piperidin-4-yloxy]-7-methoxy-chinazoline,4-[(3-Ethinyl-phenyl)amino]-6-{1-[(morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-chinazoline,4-[(3-chlor-4-fluor-phenyl)amino]-6-{1-[(cis-2,6-dimethyl-morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-chinazoline,4-[(3-chlor-4-fluor-phenyl)amino]-6-{1-[(2-methyl-morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-chinazoline,4-[(3-chlor-4-fluor-phenyl)amino]-6-{1-[(S,S)-(2-oxa-5-aza-bicyclo[2.2.1]hept-5-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-chinazoline,4-[(3-chlor-4-fluor-phenyl)amino]-6-{1-[(N-methyl-N-2-methoxyethyl-amino)carbonyl]-piperidin-4-yloxy}-7-methoxy-chinazoline,4-[(3-chlor-4-fluor-phenyl)amino]-6-(1-ethyl-piperidin-4-yloxy)-7-methoxy-chinazoline,4-[(3-chlor-4-fluor-phenyl)amino]-6-{1-[(2-methoxyethyl)carbonyl]-piperidin-4-yloxy}-7-methoxy-chinazoline,4-[(3-chlor-4-fluor-phenyl)amino]-6-{1-[(3-methoxypropyl-amino)-carbonyl]-piperidin-4-yloxy}-7-methoxy-chinazoline,4-[(3-chlor-4-fluor-phenyl)amino]-6-[cis-4-(N-methansulfonyl-N-methyl-amino)-cyclohexan-1-yloxy]-7-methoxy-chinazoline,4-[(3-chlor-4-fluor-phenyl)amino]-6-[cis-4-(N-acetyl-N-methyl-amino)-cyclohexan-1-yloxy]-7-methoxy-chinazoline,4-[(3-chlor-4-fluor-phenyl)amino]-6-(trans-4-methylamino-cyclohexan-1-yloxy)-7-methoxy-chinazoline,4-[(3-chlor-4-fluor-phenyl)amino]-6-[trans-4-(N-methansulfonyl-N-methyl-amino)-cyclohexan-1-yloxy]-7-methoxy-chinazoline,4-[(3-chlor-4-fluor-phenyl)amino]-6-(trans-4-dimethylamino-cyclohexan-1-yloxy)-7-methoxy-chinazoline,4-[(3-chlor-4-fluor-phenyl)amino]-6-(trans-4-{N-[(morpholin-4-yl)carbonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-chinazoline,4-[(3-chlor-4-fluor-phenyl)amino]-6-[2-(2,2-dimethyl-6-oxo-morpholin-4-yl)-ethoxy]-7-[(S)-(tetrahydrofuran-2-yl)methoxy]-chinazoline,4-[(3-chlor-4-fluor-phenyl)amino]-6-(1-methansulfonyl-piperidin-4-yloxy)-7-methoxy-chinazoline,4-[(3-chlor-4-fluor-phenyl)amino]-6-(1-cyano-piperidin-4-yloxy)-7-methoxy-chinazoline,Cetuximab, Trastuzumab, ABX-EGF and Mab ICR-62. These compounds may beused, as available, in the form of their racemates, enantiomers ordiastereoisomers, or in the form of pharamacologically acceptable acidaddition salts thereof, or in the form of their solvates and/orhydrates.

These compounds are disclosed in the prior art, e.g. in WO 96/30347, WO97/02266, WO 99/35146, WO 00/31048, WO 00/78735, WO 01/34574, WO01/61816, WO 01/77104, WO02/18351, WO 02/18372, WO 02/18373, WO02/18376, WO 02/50043, WO 03/082290, Cancer Research 2004, 64:11(3958-3965), Am J Health-Syst Pharm 2000, 57(15), 2063-2076, ClinicalTherapeutics 1999, 21(2), 309-318, WO 98/50433, and WO 95/20045.

Endothelin-antagonists may preferably be selected from the groupconsisting of tezosentan, bosentan, enrasentan, sixtasentan, T-0201,BMS-193884, K-8794, PD-156123, PD-156707, PD-160874, PD-180988, S-0139and ZD-1611. Any reference to endothelin-antagonists within the scope ofthe present invention includes a reference to the salts, preferablypharmacologically acceptable acid addition salts, or derivatives whichmay be formed from the endothelin-antagonists.

These combinations may be administered either simultaneously orsequentially.

For pharmaceutical use the compounds according to the invention arepreferably used for warm-blooded vertebrates, particularly humans, indoses of 0.0001-100 mg/kg of body weight.

These compounds may be administered either on their own or inconjunction with other active substances by intravenous, subcutaneous,intramuscular, intraperitoneal or intranasal route, by inhalation, ortransdermally, or orally, whilst aerosol formulations are particularlysuitable for inhalation.

For administration they are formulated with one or more conventionalinert solid, semisolid or liquid carriers e.g. with starch, differenttypes of cellulose, lactose, mannitol, sorbitol, glucose, calciumphosphate, hard fat, fatty alcohols, glycerol, medium chainedtriglycerides and related esters, polyethylene glycol, refined specialtyoils, water, water/ethanol, water/glycerol, water/sorbitol,water/polyethylene glycol, propylene glycol, and/or functionalexcipients, e.g. with polyvinylpyrrolidone,hydroxypropylmethylcellulose, sodium carboxymethylcellulose, sodiumstarch glycolate, silicon dioxide, polysorbates, poloxamers, gelucires,magnesium stearate, citric acid, tartaric acid, or suitable mixturesthereof in conventional galenic preparations such as plain or coatedtablets, capsules, powders, injectable solutions, ampoules, suspensions,solutions, sprays or suppositories.

The following examples of formulations illustrate the present inventionwithout representing a limitation of its scope.

Example F1: Coated Tablet Containing 75 mg of Active Substance

Composition

1 tablet core contains: active substance 75.0 mg calcium phosphate 131.0mg  polyvinylpyrrolidone 10.0 mg carboxymethylcellulose sodium 10.0 mgsilicon dioxide  2.5 mg magnesium stearate  1.5 mg 230.0 mg 

Preparation (Direct Compression)

The active substance is mixed with all components, sieved and compressedin a tablet-making machine to form tablets of the desired shape.

-   -   Weight of core: 230 mg    -   Appearance of core: 9 mm, biconvex

The tablet cores thus produced are coated with a film consistingessentially of hydroxypropylmethylcellulose.

-   -   Weight of coated tablet: 240 mg.

Example F2: Tablet Containing 100 mg of Active Substance

Composition

1 tablet contains: active substance 100.0 mg  lactose 80.0 mg cornstarch 34.0 mg hydroxypropylmethylcellulose  4.0 mg magnesium stearate 2.0 mg 220.0 mg 

Preparation (Wet Granulation)

The active substance, lactose and starch are mixed together anduniformly moistened with an aqueous solution of thehydroxypropylmethylcellulose. After the moist composition has beenscreened (2.0 mm mesh size) and dried in a rack-type drier at 50° C. itis screened again (1.5 mm mesh size) and the lubricant is added. Thefinished mixture is compressed to form tablets.

-   -   Weight of tablet: 220 mg    -   Appearance of tablet: 10 mm, flat faced with bevelled edges and        breaking notch on one side.

Example F3: Tablet Containing 150 mg of Active Substance

Composition

1 tablet contains: active substance 150.0 mg  lactose 85.0 mgmicrocrystalline cellulose 40.0 mg polyvinylpyrrolidone 10.0 mg silicondioxide 10.0 mg magnesium stearate  5.0 mg 300.0 mg 

Preparation (Dry Granulation)

The active substance mixed with lactose, polyvinylpyrrolidone, and partsof the microcrystalline cellulose, magnesium stearate is compacted e.g.on a roller compactor. The ribbons are broken up in fine granulesthrough a screen with a mesh size of 0.8 mm. After subsequent sievingthrough a screen with a mesh size of 0.5 mm and blending with theremaining components, tablets are pressed from the mixture.

-   -   Weight of tablet: 300 mg    -   Appearance of tablet: 10 mm, flat

Example F4: Hard Gelatine Capsule Containing 150 mg of Active Substance

Composition

1 capsule contains: active substance 150.0 mg  lactose 85.0 mgmicrocrystalline cellulose 40.0 mg polyvinylpyrrolidone 10.0 mg silicondioxide 10.0 mg magnesium stearate  5.0 mg 300.0 mg 

Preparation

The active substance mixed with lactose, polyvinylpyrrolidone, and partsof the microcrystalline cellulose, magnesium stearate is compacted e.g.on a roller compactor. The ribbons are broken up in fine granulesthrough a screen with a mesh size of 0.8 mm. After subsequent sievingthrough a screen with a mesh size of 0.5 mm and blending with theremaining components, the finished mixture is packed into size 1 hardgelatine capsules.

-   -   Capsule filling: approx. 300 mg    -   Capsule shell: size 1 hard gelatine capsule.

Example F5: Suppository Containing 150 mg of Active Substance

1 suppository contains: active substance 150.0 mg polyethyleneglycol1500 800.0 mg polyethyleneglycol 6000 850.0 mg polyoxyl 40 hydrogenatedcastor oil 200.0 mg 2,000.0 mg  

Preparation

After the suppository mass has been melted the active substance ishomogeneously distributed therein and the melt is poured into chilledmoulds.

Example F6: Suspension Containing 50 mg of Active Substance

100 ml of suspension contains active substance 1.00 gcarboxymethylcellulose sodium 0.10 g methyl p-hydroxybenzoate 0.05 gpropyl p-hydroxybenzoate 0.01 g glucose 10.00 g glycerol 5.00 g 70%sorbitol solution 20.00 g flavouring 0.30 g dist. water ad 100 ml

Preparation

The distilled water is heated to 70° C. The methyl and propylp-hydroxybenzoates together with the glycerol and sodium salt ofcarboxymethylcellulose are dissolved therein with stirring. The solutionis cooled to ambient temperature and the active substance is added andhomogeneously dispersed therein with stirring. After the sugar, thesorbitol solution and the flavouring have been added and dissolved, thesuspension is evacuated with stirring to eliminate air.

Thus, 5 ml of suspension contains 50 mg of active substance.

Example F7: Ampoule Containing 10 mg Active Substance

Composition

active substance 10.0 mg 0.01N hydrochloric acid q.s. double-distilledwater ad 2.0 ml

Preparation

The active substance is dissolved in the necessary amount of 0.01 N HCl,made isotonic with sodium chloride, filtered sterile and transferredinto a 2 ml ampoule.

Example F8: Ampoule Containing 50 mg of Active Substance

Composition

active substance 50.0 mg 0.01N hydrochloric acid q.s. double-distilledwater ad 10.0 ml

Preparation

The active substance is dissolved in the necessary amount of 0.01 N HCl,made isotonic with sodium chloride, filtered sterile and transferredinto a 10 ml ampoule.

Example F9: Capsule for Powder Inhalation Containing 5 mg of ActiveSubstance

1 capsule contains active substance  5.0 mg lactose for inhalation 15.0mg 20.0 mg

Preparation

The active substance is mixed with lactose for inhalation. The mixtureis packed into capsules in a capsule-making machine (weight of the emptycapsule approx. 50 mg).

weight of capsule: 70.0 mg

size of capsule=size 3

Example F10: Solution for Inhalation for a Hand-Held NebuliserContaining 2.5 mg Active Substance

1 spray contains active substance 2.500 mg benzalkonium chloride 0.001mg 1N hydrochloric acid q.s. ethanol/water (50/50) ad 15.000 mg

Preparation

The active substance and benzalkonium chloride are dissolved inethanol/water (50/50). The pH of the solution is adjusted with 1Nhydrochloric acid. The resulting solution is filtered and transferredinto suitable containers for use in hand-held nebulisers (cartridges).

Contents of the container: 4.5 g

What is claimed is:
 1. A method for treating fibrosis in rheumatoidarthritis, comprising administering to patient in need thereof atherapeutically effective amount of3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone,or a salt thereof.
 2. The method of claim 1 wherein3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinoneis in the form of a monoethanesulfonate salt.
 3. The method of claim 1further comprising administering an additional pharmacologically activesubstance selected from the group consisting of anticholinergic agents,beta-2 mimetics, steroids, PDE-IV inhibitors, p38 MAP kinase inhibitors,NK1 antagonists, LTD4 antagonists, EGFR inhibitors andendothelin-antagonists.
 4. The method of claim 3, wherein the3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone,or salt thereof, and the additional pharmacologically active substancetogether comprise a pharmaceutical composition that further comprisesone or more pharmaceutically acceptable carriers or excipients.